G2Cdb::Gene report

Gene id
G00002430
Gene symbol
MYH6 (HGNC)
Species
Homo sapiens
Description
myosin, heavy chain 6, cardiac muscle, alpha
Orthologue
G00001181 (Mus musculus)

Databases (9)

Curated Gene
OTTHUMG00000028755 (Vega human gene)
Gene
ENSG00000092054 (Ensembl human gene)
4624 (Entrez Gene)
172 (G2Cdb plasticity & disease)
MYH6 (GeneCards)
Literature
160710 (OMIM)
Marker Symbol
HGNC:7576 (HGNC)
Protein Expression
1239 (human protein atlas)
Protein Sequence
P12883 (UniProt)

Diseases (6)

Disease Nervous effect Mutations Found Literature Mutations Type Genetic association?
D00000235: Hypertrophic cardiomyopathy N Y (15010274) Polymorphism (P) Y
D00000255: Myosin storage myopathy N Y (15136674) Single nucleotide polymorphism (SNP) Y
D00000209: Myopathy (early onset distal) N Y (15322983) Polymorphism (P) Y
D00000235: Hypertrophic cardiomyopathy N Y (15358028) Microinsertion (MI) Y
D00000235: Hypertrophic cardiomyopathy N Y (15358028) Deletion (D) Y
D00000236: Hypertrophic cardiomyopathy (familial) N Y (15483641) Polymorphism (P) Y
D00000236: Hypertrophic cardiomyopathy (familial) N Y (15528230) Polymorphism (P) Y
D00000235: Hypertrophic cardiomyopathy N Y (15563892) Polymorphism (P) Y
D00000235: Hypertrophic cardiomyopathy N Y (15569455) Unknown (?) Y
D00000255: Myosin storage myopathy N Y (15699387) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (15706574) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (15769782) Microinsertion (MI) Y
D00000235: Hypertrophic cardiomyopathy N Y (15819282) Unknown (?) Y
D00000235: Hypertrophic cardiomyopathy N Y (15856146) Microinsertion (MI) Y
D00000236: Hypertrophic cardiomyopathy (familial) N Y (15858117) Microinsertion (MI) Y
D00000235: Hypertrophic cardiomyopathy N Y (15940186) Polymorphism (P) Y
D00000235: Hypertrophic cardiomyopathy N Y (16137545) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (16504640) Polymorphism (P) Y
D00000235: Hypertrophic cardiomyopathy N Y (16630449) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (16650083) Microinsertion (MI) Y
D00000255: Myosin storage myopathy N Y (16684601) Single nucleotide polymorphism (SNP) Y
D00000284: Increased left ventricular wall thickness N Y (16754800) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (16858239) Microinsertion (MI) Y
D00000235: Hypertrophic cardiomyopathy N Y (16938236) Single nucleotide polymorphism (SNP) Y
D00000236: Hypertrophic cardiomyopathy (familial) N Y (17081393) No mutation found (N) N
D00000235: Hypertrophic cardiomyopathy N Y (17097032) Single nucleotide polymorphism (SNP) Y
D00000255: Myosin storage myopathy N Y (17118657) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (17125710) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (17288815) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (17288815) Microinsertion (MI) Y
D00000255: Myosin storage myopathy N Y (17336526) Single nucleotide polymorphism (SNP) Y
D00000256: Scapulo-peroneal myopathy N Y (17336526) Single nucleotide polymorphism (SNP) Y
D00000235: Hypertrophic cardiomyopathy N Y (17347475) No mutation found (N) N

References

  • MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.

    Pegoraro E, Gavassini BF, Borsato C, Melacini P, Vianello A, Stramare R, Cenacchi G and Angelini C

    Department of Neurosciences, University of Padova, Italy. elena.pegoraro@unipd.it

    In order to characterize, at the clinical, molecular and imaging level, myopathies due to MYH7 gene mutations, MYH7 gene analysis was conducted by RT-PCR/SSCP/sequencing in two patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapulo-peroneal myopathy of unknown etiology. MYH7 gene studies revealed the 5533C>T mutation (Arg1845Trp) in both myosin storage myopathy and in 2 of the 17 scapulo-peroneal patients studied. 5533C>T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in our cohort of patients included asymptomatic hyperCKemia, scapulo-peroneal myopathy and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies in only half of biopsied patients (2/4). In conclusion, phenotypic and histopathological variability may underlie MYH7 gene mutation and the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations.

    Funded by: Telethon: GTF02009

    Neuromuscular disorders : NMD 2007;17;4;321-9

  • Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy.

    Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT and Marian AJ

    Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX 77030, USA.

    Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.

    Funded by: NHLBI NIH HHS: P50 HL054313, P50 HL054313-060012, P50 HL054313-070012, P50 HL054313-080012, P50 HL054313-08S10012, P50 HL054313-090012, P50 HL054313-100012, R01 HL068884, R01 HL068884-01, R01 HL068884-02, R01 HL068884-03, R01 HL068884-04, R01 HL068884-05, R01-HL68884

    Circulation research 2007;100;6;766-8

  • Myosin storage (hyaline body) myopathy: a case report.

    Shingde MV, Spring PJ, Maxwell A, Wills EJ, Harper CG, Dye DE, Laing NG and North KN

    Department of Pathology, University of Sydney, Australia. meena.shingde@email.cs.nsw.gov.au

    Myosin storage myopathy/hyaline body myopathy is a rare congenital myopathy, with less than 30 cases reported in the literature. It is characterised by the presence of subsarcolemmal hyaline bodies in type 1 muscle fibres and predominantly proximal muscle weakness. Recently, a single mutation (Arg1845Trp) in the slow/beta-cardiac myosin heavy chain gene (MYH7) was identified in four unrelated probands from Sweden and Belgium. The clinical severity and age of onset was variable, despite the same disease-causing mutation and similar histological findings. Here, we report the clinical and morphological findings of two brothers of English/Scottish background with the Arg1845Trp mutation in MYH7. This case report adds to the clinical description of this rare disorder and confirms that Arg1845Trp is a common mutation associated with this phenotype, at least in the White European population.

    Neuromuscular disorders : NMD 2006;16;12;882-6

  • [Comparative study of gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy].

    Pan GZ, Liu WL, Hu DY, Xie WL, Zhu TG, Li L, Li CL and Bian H

    Department of Cardiology, Fuxing Hospital Affiliated to Capital University of Medical Sciences, Beijing 100038, China.

    Objective: To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM).

    Methods: Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites.

    Results: (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively.

    Conclusion: MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM.

    Zhonghua yi xue za zhi 2006;86;42;2998-3001

  • Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

    Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM and Jiang WP

    Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, China. yangjhsz@163.com

    Background: Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype.

    Methods: The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed.

    Results: The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated.

    Conclusion: The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

    Chinese medical journal 2006;119;21;1785-9

  • [Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].

    Laredo R, Monserrat L, Hermida-Prieto M, Fernández X, Rodríguez I, Cazón L, Alvariño I, Dumont C, Piñón P, Peteiro J, Bouzas B and Castro-Beiras A

    Servicio de Cardiología, Complejo Hospitalario Universitario Juan Canalejo e Instituto Universitario de Ciencias de la Salud de la Universidad de A Coruña, A Coruña, Spain.

    To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype.

    Methods: Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded.

    Results: A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness > or = 30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged < or = 36 years. Sudden death had occurred in eight members of four families: four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P.

    Conclusions: MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified.

    Revista espanola de cardiologia 2006;59;10;1008-18

  • A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.

    Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, Fantini S, Baldini K, Torricelli F and Cecchi F

    Genetic Diagnostic Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. citogenbibl3@ao-careggi.toscana.it

    Background: Mutations causing hypertrophic cardiomyopathy (HCM) have been described in nine different genes of the sarcomere. Three genes account for most known mutations: beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3) and cardiac troponin T (TNNT2). Their prevalence in Italian HCM patients is unknown. Thus, we prospectively assessed a molecular screening strategy of these three genes in a consecutive population with HCM from two Italian centres.

    Methods: Comprehensive screening of MYBPC3, MYH7 and TNNT2 was performed in 88 unrelated HCM patients by denaturing high-performance liquid chromatography and automatic sequencing.

    Results: We identified 32 mutations in 50 patients (57%); 16 were novel. The prevalence rates for MYBPC3, MYH7 and TNNT2 were 32%, 17% and 2%, respectively. MYBPC3 mutations were 18, including two frameshift, five splice-site and two nonsense. All were 'private' except insC1065 and R502Q, present in three and two patients, respectively. Moreover, E258K was found in 14% of patients, suggesting a founder effect. MYH7 mutations were 12, all missense; seven were novel. In TNNT2, only two mutations were found. In addition, five patients had a complex genotype [i.e. carried a double MYBPC3 mutation (n = 2), or were double heterozygous for mutations in MYBPC3 and MYH7 (n = 3)].

    Conclusions: The first comprehensive evaluation of MYBPC3, MYH7 and TNNT2 in an Italian HCM population allowed a genetic diagnosis in 57% of the patients. These data support a combined analysis of the three major sarcomeric genes as a rational and cost-effective initial approach to the molecular screening of HCM.

    Journal of cardiovascular medicine (Hagerstown, Md.) 2006;7;8;601-7

  • [Familiar hypertrophic cardiomyopathy caused by a IVS15-1G > A mutation in cardiac myosin-binding protein C gene].

    Zou YB, Wang JZ, Wu GR, Song L, Wang SX, Yu H, Zhang Q, Wang H and Hui RT

    German Laboratory for Molecular Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Objective: To detect the disease-causing gene mutation of hypertrophic cardiomyopathy (HCM) in a Chinese family and to analyze the correlation of the genotype and the phenotype.

    Methods: One family affected with HCM was studied. The clinical data including symptom, physical examination, echocardiography and electrocardiography were collected. The full encoding exons and flanking sequences of beta-myosin heavy chain gene (MYH7) and cardiac myosin-binding protein C gene (MYBPC3) were amplified with PCR and the products were sequenced.

    Results: A G8887A mutation, which is an acceptor splicing site of intron 15 (IVS15-1G > A) in MYBPC3 (gi: Y10129) was identified in 6 out of 11 family members. Three mutation carriers developed HCM at 48 - 75 years old with mild chest pain, chest distress and asymmetric septal hypertrophy (13 - 14 mm) and remaining mutation carriers are free of HCM. No mutation was identified in MYH7 gene.

    Conclusion: HCM caused by the IVS15-1G > A mutation is a benign phenotype. It is helpful to screen MYBPC3 gene mutation in late-onset HCM patients with mild symptoms.

    Zhonghua xin xue guan bing za zhi 2006;34;8;699-702

  • [Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-myosin heavy-chain gene].

    Mora R, Merino JL, Peinado R, Olias F, García-Guereta L, del Cerro MJ, Tarín MN and Molano J

    Unidad de Genética Molecular, Servicio de Bioquímica, Hospital Universitario La Paz, Madrid, España.

    The aim of this study was to identify mutations in the cardiac heavy-chain beta-myosin gene (MYH7b) in a group of Spanish patients with hypertrophic cardiomyopathy. The study included 36 families with at least one member who had hypertrophic cardiomyopathy. DNA from exons 3 to 24 of the MYH7b gene was sequenced. Two mutations were identified: Arg858Cys and Met515Val. They occurred in two families, one of which was of Moroccan origin. This corresponds to a MYH7b gene mutation frequency of less than 5%. In contrast to findings in other Caucasian populations, MYH7b gene mutation occurred infrequently in this group of Spanish families with hypertrophic cardiomyopathy.

    Revista espanola de cardiologia 2006;59;8;846-9

  • Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study.

    Morita H, Larson MG, Barr SC, Vasan RS, O'Donnell CJ, Hirschhorn JN, Levy D, Corey D, Seidman CE, Seidman JG and Benjamin EJ

    The Program in Genomics Applications: CardioGenomics Group--Department of Genetics, NRB Room 256, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    Background: Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown.

    We studied 1862 unrelated participants (52% women; age, 59+/-9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy-causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT (maximum LVWT >13 mm). Fifty eligible participants (9 women) had unexplained increased LVWT. We detected 8 mutations in 9 individuals (2 women); 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3), and 1 GLA mutation. In individuals with increased LVWT, participants with sarcomere protein and storage mutations were clinically indistinguishable from those without mutations.

    Conclusions: In a community-based cohort, about 3% of eligible participants had increased LVWT, of whom 18% had sarcomere protein or lipid storage gene mutations. Increased LVWT in the community is a very heterogeneous condition, which sometimes may arise from single-gene variants in one of a number of genes.

    Funded by: NHLBI NIH HHS: K24-HL04334, N01-HC 25195, U01 HL 66582; NINDS NIH HHS: 5R01-NS 17950

    Circulation 2006;113;23;2697-705

  • Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred.

    Dye DE, Azzarelli B, Goebel HH and Laing NG

    Molecular Neurogenetics Laboratory, Centre for Medical Research, West Australian Institute for Medical Research, University of Western Australia M519, 'B' Block, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia.

    Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579-585] in two siblings as 'familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene (MYH7) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopathy.

    Neuromuscular disorders : NMD 2006;16;6;357-60

  • Genotype-phenotype correlation of R870H mutation in hypertrophic cardiomyopathy.

    Tanjore RR, Sikindlapuram AD, Calambur N, Thakkar B, Kerkar PG and Nallari P

    Clinical genetics 2006;69;5;434-6

  • [Analysis of MYH7, MYBPC3 and TNNT2 gene mutations in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype].

    Liu WL, Xie WL, Hu DY, Zhu TG, Li YT, Sun YH, Li CL, Li L, Li TC, Bian H, Tong QG, Yang SN, Fan RY and Cui W

    Cardiology Division, People's Hospital, Peking University, Beijing 100044, China.

    Objective: The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM).

    Methods: There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype.

    Results: Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2.

    Conclusions: Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM.

    Zhonghua xin xue guan bing za zhi 2006;34;3;202-7

  • Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.

    Poutanen T, Tikanoja T, Jääskeläinen P, Jokinen E, Silvast A, Laakso M and Kuusisto J

    Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland. tuija.poutanen@koti.tpo.fi

    Objectives: We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children.

    Background: In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations.

    Methods: All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children.

    Results: Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children.

    Conclusions: In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

    American heart journal 2006;151;3;725.e1-725.e9

  • Characteristics of the beta myosin heavy chain gene Ala26Val mutation in a Chinese family with hypertrophic cardiomyopathy.

    Liu SX, Hu SJ, Sun J, Wang J, Wang XT, Jiang Y and Cai J

    Department of Cardiovascular Medicine, The First Affiliated Hospital, College of Medical Science, Zhejiang University, QingChun Road 33, Hangzhou 310003, PR China. s0hu0001@hotmail.com

    Background: Genotype-phenotype studies have suggested that some mutations of genes encoding various components of the cardiac sarcomere cause hypertrophic cardiomyopathy (HCM) and are associated with the prognosis of patients with HCM. The aims of this study were to investigate the gene mutations of exons in the cardiac beta myosin heavy chain (MYH7) gene, the troponin T (TNNT2) gene, and the brain natriuretic peptide (BNP) gene, as well as to assess the effect of these mutations on the clinical features of Chinese patients with HCM.

    Methods: Five unrelated Chinese families with HCM were studied. Exons 3 and 18 in the MYH7 gene, exon 9 in the TNNT2 gene, and all three exons in the BNP gene were screened with the polymerase chain reaction (PCR) for genomic DNA amplification. Further study included purification of PCR products and direct sequencing of PCR fragments by fluorescent end labeling.

    Results: A C-to-T transition in codon 26 of exon 3 in the MYH7 gene was found in one family (including four patients and five carriers), resulting in an amino acid substitution of valine (Val) for alanine (Ala). The Ala26Val mutation was of incomplete dominance (penetrance 44%). This mutation was not seen in the other four families or in the control group. Moreover, the association between the gene mutations of exon 18 in MYH7, of exon 9 of TNNT2, and of all three exons in BNP and HCM was not found in the populations we studied.

    Conclusions: The missense mutation Ala26Val found in this one Chinese family was associated with a mild phenotype of HCM. The genetic and phenotypic heterogeneity of HCM exists in the Chinese population. It suggests that genetic and environmental factors may be involved in the pathogenesis of HCM.

    European journal of internal medicine 2005;16;5;328-33

  • Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

    Perrot A, Schmidt-Traub H, Hoffmann B, Prager M, Bit-Avragim N, Rudenko RI, Usupbaeva DA, Kabaeva Z, Imanov B, Mirrakhimov MM, Dietz R, Wycisk A, Tendera M, Gessner R and Osterziel KJ

    Kardiologie am Campus Buch und Virchow-Klinikum, Charité-Universitätsmedizin Berlin und Max-Delbrück-Centrum für Molekulare Medizin, Wiltbergstrasse 50, 13125 Berlin, Germany. perrot@fvk-berlin.de

    Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol. The DNA of the patients was systematically analyzed in the whole coding region of the MYH7 gene using PCR, single-strand conformation polymorphism analysis, and automated sequencing. Eleven different missense mutations (including seven novel ones) in 11 unrelated patients were identified, showing a mutation frequency of 7.5% in the study population. We further examined the families of five patients (three of German, one of Polish, and one of Kyrgyz origin) with 32 individuals in total. We observed a clear, age-dependent penetrance with onset of disease symptoms in the fourth decade of life. Genotype-phenotype correlations were different for each mutation, whereas the majority was associated with an intermediate/malign phenotype. In conclusion, we report a systematic molecular screening of the complete MYH7 gene in a large group of consecutive HCM patients, leading to a genetic diagnosis in 38 individuals. Information about the genotype in an individual from one family could be very useful for the clinician, especially when dealing with healthy relatives in doubt of their risk about developing HCM. The increasing application of genetic screening and the increasing knowledge about genotype-phenotype correlations will hopefully lead to an improved clinical management of HCM patients.

    Journal of molecular medicine (Berlin, Germany) 2005;83;6;468-77

  • Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease.

    Yu B, Sawyer NA, Caramins M, Yuan ZG, Saunderson RB, Pamphlett R, Richmond DR, Jeremy RW and Trent RJ

    Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital and Central Clinical School, The University of Sydney, Missenden Road, Camperdown, NSW 2050, Australia. bingy@med.usyd.edu.au

    Aims: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) as a high throughput tool in: (1) DNA mutation detection in familial hypertrophic cardiomyopathy (FHC), and (2) single nucleotide polymorphism (SNP) discovery and validation in sporadic motor neurone disease (MND).

    Methods: The coding sequence and intron-exon boundaries of the cardiac beta myosin heavy chain gene (MYH7) were screened by DHPLC for mutation identification in 150 unrelated patients diagnosed with FHC. One hundred and forty patients with sporadic MND were genotyped for the A67T SNP in the poliovirus receptor gene. All DHPLC positive signals were confirmed by conventional methods.

    Results: Mutation screening of MYH7 covered 10 kb with a total of 5700 amplicons, and more than 6750 DHPLC injections were completed within 35 days. The causative mutation was identified in 14% of FHC cases, including seven novel missense mutations (L227V, E328G, K351E, V411I, M435T, E894G, and E927K). Genotyping of the A67T SNP was performed at two different temperatures both in MND cases and 280 controls. This coding SNP was found more frequently in MND cases (13.6%) than in controls (6.8%). Furthermore, 19 and two SNPs were identified in MYH7 and the poliovirus receptor gene, respectively, during DHPLC screening.

    Conclusions: DHPLC is a high throughput, sensitive, specific, and robust platform for the detection of DNA variants, such as disease causing mutations or SNPs. It enables rapid and accurate screening of large genomic regions.

    Journal of clinical pathology 2005;58;5;479-85

  • High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.

    Tian H, Emrich CA, Scherer JR, Mathies RA, Andersen PS, Larsen LA and Christiansen M

    Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.

    A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.

    Funded by: NHGRI NIH HHS: HG 01399

    Electrophoresis 2005;26;9;1834-42

  • Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

    Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N and Komajda M

    INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France. villard@chups.jussieu.fr

    Aims: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.

    A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).

    Conclusion: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.

    European heart journal 2005;26;8;794-803

  • Sarcomeric genotyping in hypertrophic cardiomyopathy.

    Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ and Ackerman MJ

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.

    Objective: To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

    Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

    Results: The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.

    Conclusions: Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

    Mayo Clinic proceedings 2005;80;4;463-9

  • Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.

    Alpert NR, Mohiddin SA, Tripodi D, Jacobson-Hatzell J, Vaughn-Whitley K, Brosseau C, Warshaw DM and Fananapazir L

    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA.

    Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding beta-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V(actin)) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V(actin) was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V(actin) for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V(actin) may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.

    Funded by: NHLBI NIH HHS: P01-HL-59408

    American journal of physiology. Heart and circulatory physiology 2005;288;3;H1097-102

  • Myosin storage myopathy: slow skeletal myosin (MYH7) mutation in two isolated cases.

    Laing NG, Ceuterick-de Groote C, Dye DE, Liyanage K, Duff RM, Dubois B, Robberecht W, Sciot R, Martin JJ and Goebel HH

    Centre for Neuromuscular and Neurologic Disorders, Australian Neuromuscular Research Institute and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Australia. nlaing@cyllene.uwa.edu.au

    Myosin storage myopathy is a congenital myopathy characterized by subsarcolemmal hyaline bodies in type 1 muscle fibers, which are ATPase positive and thus contain myosin. Mutations recently were identified in the type 1 muscle fiber myosin gene (MYH7) in Swedish and Saudi families with myosin storage myopathy. The authors have identified the arginine 1845 tryptophan mutation found in the Swedish families in two isolated Belgian cases, indicating a critical role for myosin residue arginine 1845.

    Neurology 2005;64;3;527-9

  • One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region.

    Hougs L, Havndrup O, Bundgaard H, Køber L, Vuust J, Larsen LA, Christiansen M and Andersen PS

    Department of Clinical Biochemistry, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark.

    Familial hypertrophic cardiomyopathy (FHC) is, in most cases, a disease of the sarcomere, caused by a mutation in one of 10 known sarcomere disease genes. More than 266 mutations have been identified since 1989. The FHC disease gene first characterized MYH7, encodes the cardiac beta-myosin heavy chain, and contains more than 115 of these mutations. However, in most studies, only the region encoding the globular head and the hinge region of the mature cardiac beta-myosin heavy chain have been investigated. Furthermore, most studies carries out screening for mutations in the most prevalent disease genes, and discontinues screening when an apparent disease-associated mutation has been identified. The aim of the present study was to screen for mutations in the rod region of the MYH7 gene in all probands of the cohort, regardless of the known genetic status of the proband. Three disease-causing mutations were identified in the rod region in four probands using capillary electrophoresis single-strand conformation polymorphism as a screening method. All mutations were novel: N1327K, R1712W, and E1753K. Two of the probands had already been shown to carry other FHC-associated mutations. In conclusion, we show that in the Danish cohort we find one third of all MYH7 mutations in the rod-encoding region and we find that two of the patients carrying these mutations also carry mutations in other FHC disease genes stressing the need for a complete screening of all known disease genes in FHC-patients.

    European journal of human genetics : EJHG 2005;13;2;161-5

  • Mutations profile in Chinese patients with hypertrophic cardiomyopathy.

    Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J and Hui R

    Sino-German Laboratory for Molecular Medicine, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Background: There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China, but the genetic basis is presently unknown.

    Methods: We investigated 100 independent patients with HCM (proband 51, sporadic 49) by sequencing the three most frequent HCM-causing genes (MYH7, MYBPC3, TNNT2).

    Results: Thirty-four patients (34%) carried 25 types of mutations in the selected genes, most (14/25) were newly identified. MYH7 and MYBPC3 accounted for 41% and 18% of the familial HCM, respectively. TNNT2 mutations only caused 2% of the familial HCM. These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM. MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations. The patients carrying R663C, Q734P, E930K in MYH7 and R130C in TNNT2 expressed malignant phenotype. R403Q in MYH7, the most common hot and malignant mutation in Caucasians, was not identified in Chinese.

    Conclusion: We confirmed the diversity of mutation profile in different populations and suggest that a global registry of HCM mutations and their phenotypes is necessary to correlate genotype with phenotype.

    Clinica chimica acta; international journal of clinical chemistry 2005;351;1-2;209-16

  • [The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

    Seleznev DM, Gabrusenko SA, Parfenova EV, Naumov VG, Stambol'skiĭ DV and Tkachuk VA

    One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands). DHPLC was used with subsequent sequencing of DNA fragments. Genetic defects of beta-myosin heavy chain were found more than in every 10-th patient. These defects were represented by 13 mutations (Ala729Pro mutation was found twice). Phenotypes of majority of known mutations in Russian population did not differ substantially from their phenotypes in other populations. Six mutations had not been previously described; most of them were associated with especially severe clinical and hemodynamic signs and relatively unfavorable course of the disease. Thus beta-myosin heavy chain gene mutation play important role in etiology of HCMP in patients in Russia.

    Kardiologiia 2005;45;4;15-20

  • [Mutations in beta myosin heavy chain gene: two mutations in Chinese with familial hypertrophic cardiomyopathy and the correlation between the genotype and phenotype].

    Xie WL, Liu WL, Hu DY, Cui W, Zhu TG, Li CL, Sun YH, Li L, Li TC, Bian H and Tong QG

    Department of Cardiology, Second Hospital, Peking University, Beijing 100044, China.

    Objective: To study the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype.

    Methods: Samples of peripheral blood were collected from five Chinese patients with HCM in whose families at least 2 HCM patients existed. The exon in the functional regions of the beta myosin heavy chain gene (beta-MHC) were amplified with PCR and the products were sequenced. The relation between the genotype and phenotype was analyzed.

    Results: Two mutations were first identified. Eighty controls were normal in the genetic test.

    Conclusion: beta-MHC may be the main disease-causing gene. Two mutations have different phenotypes. In one family, the identical mutation has different phenotypes and prognoses. The heterogeneity of phenotype suggests that multiple factors be involved in the pathogenesis.

    Zhonghua yi xue za zhi 2004;84;19;1610-3

  • Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).

    Meredith C, Herrmann R, Parry C, Liyanage K, Dye DE, Durling HJ, Duff RM, Beckman K, de Visser M, van der Graaff MM, Hedera P, Fink JK, Petty EM, Lamont P, Fabian V, Bridges L, Voit T, Mastaglia FL and Laing NG

    Centre for Human Genetics, Edith Cowan University, Perth, Australia.

    We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.

    Funded by: NINDS NIH HHS: K08 NS042743, K08NS42743, R01NS33645, R01NS36177, R01NS38713

    American journal of human genetics 2004;75;4;703-8

  • Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

    Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ and Ackerman MJ

    Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    Objectives: We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).

    Background: Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.

    Methods: Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.

    Results: Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).

    Conclusions: In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

    Funded by: NICHD NIH HHS: HD42569

    Journal of the American College of Cardiology 2004;44;3;602-10

  • Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy.

    Bohlega S, Abu-Amero SN, Wakil SM, Carroll P, Al-Amr R, Lach B, Al-Sayed Y, Cupler EJ and Meyer BF

    Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    Objective: To identify the gene and specific mutation underlying hyaline body myopathy in the family studied.

    Methods: A microsatellite-based whole genome scan was performed. Linkage analysis assumed autosomal dominant inheritance and equal allele frequencies. A candidate gene approach within the linked interval and direct sequencing were used for mutation detection.

    Results: Initial analysis indicated a maximum lod score of 3.01 at D14S1280. High-density mapping surrounding the linked locus was performed. Multipoint analysis showed that the linked region with a maximum lod score of 3.01 extended from D14S742 to D14S608 with a peak non-parametric linkage (NPL) score of 3.75 at D14S608. The myosin heavy chain genes MYH6 and MYH7 map to the region between D14S742 and D14S1280. Sequence analysis of the coding regions of MYH7 revealed an A-->T transversion at nucleotide position 25596 (M57965) resulting in a histidine-to-leucine amino acid change at residue 1904 (H1904L).

    Conclusion: Pathogenicity of the MYH7 H1904L mutation most likely results from disruption of myosin heavy chain assembly or stability of the sarcomeric protein. The MYH7 tail domain mutation results in an inclusion body myopathy with an apparent absence of hypertrophic cardiomyopathy usually associated with mutations of this gene.

    Neurology 2004;62;9;1518-21

  • Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties.

    Keller DI, Coirault C, Rau T, Cheav T, Weyand M, Amann K, Lecarpentier Y, Richard P, Eschenhagen T and Carrier L

    INSERM U582, Institut de Myologie, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtrière, 47, Bld de l'Hôpital, 75651 Paris cedex 13, France.

    Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.

    Journal of molecular and cellular cardiology 2004;36;3;355-62

Literature (55)

Pubmed - human_disease

  • MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.

    Pegoraro E, Gavassini BF, Borsato C, Melacini P, Vianello A, Stramare R, Cenacchi G and Angelini C

    Department of Neurosciences, University of Padova, Italy. elena.pegoraro@unipd.it

    In order to characterize, at the clinical, molecular and imaging level, myopathies due to MYH7 gene mutations, MYH7 gene analysis was conducted by RT-PCR/SSCP/sequencing in two patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapulo-peroneal myopathy of unknown etiology. MYH7 gene studies revealed the 5533C>T mutation (Arg1845Trp) in both myosin storage myopathy and in 2 of the 17 scapulo-peroneal patients studied. 5533C>T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in our cohort of patients included asymptomatic hyperCKemia, scapulo-peroneal myopathy and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies in only half of biopsied patients (2/4). In conclusion, phenotypic and histopathological variability may underlie MYH7 gene mutation and the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations.

    Funded by: Telethon: GTF02009

    Neuromuscular disorders : NMD 2007;17;4;321-9

  • Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy.

    Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT and Marian AJ

    Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX 77030, USA.

    Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.

    Funded by: NHLBI NIH HHS: P50 HL054313, P50 HL054313-060012, P50 HL054313-070012, P50 HL054313-080012, P50 HL054313-08S10012, P50 HL054313-090012, P50 HL054313-100012, R01 HL068884, R01 HL068884-01, R01 HL068884-02, R01 HL068884-03, R01 HL068884-04, R01 HL068884-05, R01-HL68884

    Circulation research 2007;100;6;766-8

  • Myosin storage (hyaline body) myopathy: a case report.

    Shingde MV, Spring PJ, Maxwell A, Wills EJ, Harper CG, Dye DE, Laing NG and North KN

    Department of Pathology, University of Sydney, Australia. meena.shingde@email.cs.nsw.gov.au

    Myosin storage myopathy/hyaline body myopathy is a rare congenital myopathy, with less than 30 cases reported in the literature. It is characterised by the presence of subsarcolemmal hyaline bodies in type 1 muscle fibres and predominantly proximal muscle weakness. Recently, a single mutation (Arg1845Trp) in the slow/beta-cardiac myosin heavy chain gene (MYH7) was identified in four unrelated probands from Sweden and Belgium. The clinical severity and age of onset was variable, despite the same disease-causing mutation and similar histological findings. Here, we report the clinical and morphological findings of two brothers of English/Scottish background with the Arg1845Trp mutation in MYH7. This case report adds to the clinical description of this rare disorder and confirms that Arg1845Trp is a common mutation associated with this phenotype, at least in the White European population.

    Neuromuscular disorders : NMD 2006;16;12;882-6

  • [Comparative study of gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy].

    Pan GZ, Liu WL, Hu DY, Xie WL, Zhu TG, Li L, Li CL and Bian H

    Department of Cardiology, Fuxing Hospital Affiliated to Capital University of Medical Sciences, Beijing 100038, China.

    Objective: To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM).

    Methods: Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites.

    Results: (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively.

    Conclusion: MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM.

    Zhonghua yi xue za zhi 2006;86;42;2998-3001

  • Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

    Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM and Jiang WP

    Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, China. yangjhsz@163.com

    Background: Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype.

    Methods: The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed.

    Results: The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated.

    Conclusion: The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

    Chinese medical journal 2006;119;21;1785-9

  • [Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].

    Laredo R, Monserrat L, Hermida-Prieto M, Fernández X, Rodríguez I, Cazón L, Alvariño I, Dumont C, Piñón P, Peteiro J, Bouzas B and Castro-Beiras A

    Servicio de Cardiología, Complejo Hospitalario Universitario Juan Canalejo e Instituto Universitario de Ciencias de la Salud de la Universidad de A Coruña, A Coruña, Spain.

    To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype.

    Methods: Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded.

    Results: A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness > or = 30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged < or = 36 years. Sudden death had occurred in eight members of four families: four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P.

    Conclusions: MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified.

    Revista espanola de cardiologia 2006;59;10;1008-18

  • A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.

    Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, Fantini S, Baldini K, Torricelli F and Cecchi F

    Genetic Diagnostic Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. citogenbibl3@ao-careggi.toscana.it

    Background: Mutations causing hypertrophic cardiomyopathy (HCM) have been described in nine different genes of the sarcomere. Three genes account for most known mutations: beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3) and cardiac troponin T (TNNT2). Their prevalence in Italian HCM patients is unknown. Thus, we prospectively assessed a molecular screening strategy of these three genes in a consecutive population with HCM from two Italian centres.

    Methods: Comprehensive screening of MYBPC3, MYH7 and TNNT2 was performed in 88 unrelated HCM patients by denaturing high-performance liquid chromatography and automatic sequencing.

    Results: We identified 32 mutations in 50 patients (57%); 16 were novel. The prevalence rates for MYBPC3, MYH7 and TNNT2 were 32%, 17% and 2%, respectively. MYBPC3 mutations were 18, including two frameshift, five splice-site and two nonsense. All were 'private' except insC1065 and R502Q, present in three and two patients, respectively. Moreover, E258K was found in 14% of patients, suggesting a founder effect. MYH7 mutations were 12, all missense; seven were novel. In TNNT2, only two mutations were found. In addition, five patients had a complex genotype [i.e. carried a double MYBPC3 mutation (n = 2), or were double heterozygous for mutations in MYBPC3 and MYH7 (n = 3)].

    Conclusions: The first comprehensive evaluation of MYBPC3, MYH7 and TNNT2 in an Italian HCM population allowed a genetic diagnosis in 57% of the patients. These data support a combined analysis of the three major sarcomeric genes as a rational and cost-effective initial approach to the molecular screening of HCM.

    Journal of cardiovascular medicine (Hagerstown, Md.) 2006;7;8;601-7

  • [Familiar hypertrophic cardiomyopathy caused by a IVS15-1G > A mutation in cardiac myosin-binding protein C gene].

    Zou YB, Wang JZ, Wu GR, Song L, Wang SX, Yu H, Zhang Q, Wang H and Hui RT

    German Laboratory for Molecular Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Objective: To detect the disease-causing gene mutation of hypertrophic cardiomyopathy (HCM) in a Chinese family and to analyze the correlation of the genotype and the phenotype.

    Methods: One family affected with HCM was studied. The clinical data including symptom, physical examination, echocardiography and electrocardiography were collected. The full encoding exons and flanking sequences of beta-myosin heavy chain gene (MYH7) and cardiac myosin-binding protein C gene (MYBPC3) were amplified with PCR and the products were sequenced.

    Results: A G8887A mutation, which is an acceptor splicing site of intron 15 (IVS15-1G > A) in MYBPC3 (gi: Y10129) was identified in 6 out of 11 family members. Three mutation carriers developed HCM at 48 - 75 years old with mild chest pain, chest distress and asymmetric septal hypertrophy (13 - 14 mm) and remaining mutation carriers are free of HCM. No mutation was identified in MYH7 gene.

    Conclusion: HCM caused by the IVS15-1G > A mutation is a benign phenotype. It is helpful to screen MYBPC3 gene mutation in late-onset HCM patients with mild symptoms.

    Zhonghua xin xue guan bing za zhi 2006;34;8;699-702

  • [Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-myosin heavy-chain gene].

    Mora R, Merino JL, Peinado R, Olias F, García-Guereta L, del Cerro MJ, Tarín MN and Molano J

    Unidad de Genética Molecular, Servicio de Bioquímica, Hospital Universitario La Paz, Madrid, España.

    The aim of this study was to identify mutations in the cardiac heavy-chain beta-myosin gene (MYH7b) in a group of Spanish patients with hypertrophic cardiomyopathy. The study included 36 families with at least one member who had hypertrophic cardiomyopathy. DNA from exons 3 to 24 of the MYH7b gene was sequenced. Two mutations were identified: Arg858Cys and Met515Val. They occurred in two families, one of which was of Moroccan origin. This corresponds to a MYH7b gene mutation frequency of less than 5%. In contrast to findings in other Caucasian populations, MYH7b gene mutation occurred infrequently in this group of Spanish families with hypertrophic cardiomyopathy.

    Revista espanola de cardiologia 2006;59;8;846-9

  • Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study.

    Morita H, Larson MG, Barr SC, Vasan RS, O'Donnell CJ, Hirschhorn JN, Levy D, Corey D, Seidman CE, Seidman JG and Benjamin EJ

    The Program in Genomics Applications: CardioGenomics Group--Department of Genetics, NRB Room 256, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    Background: Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown.

    We studied 1862 unrelated participants (52% women; age, 59+/-9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy-causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT (maximum LVWT >13 mm). Fifty eligible participants (9 women) had unexplained increased LVWT. We detected 8 mutations in 9 individuals (2 women); 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3), and 1 GLA mutation. In individuals with increased LVWT, participants with sarcomere protein and storage mutations were clinically indistinguishable from those without mutations.

    Conclusions: In a community-based cohort, about 3% of eligible participants had increased LVWT, of whom 18% had sarcomere protein or lipid storage gene mutations. Increased LVWT in the community is a very heterogeneous condition, which sometimes may arise from single-gene variants in one of a number of genes.

    Funded by: NHLBI NIH HHS: K24-HL04334, N01-HC 25195, U01 HL 66582; NINDS NIH HHS: 5R01-NS 17950

    Circulation 2006;113;23;2697-705

  • Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred.

    Dye DE, Azzarelli B, Goebel HH and Laing NG

    Molecular Neurogenetics Laboratory, Centre for Medical Research, West Australian Institute for Medical Research, University of Western Australia M519, 'B' Block, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia.

    Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579-585] in two siblings as 'familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene (MYH7) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopathy.

    Neuromuscular disorders : NMD 2006;16;6;357-60

  • Genotype-phenotype correlation of R870H mutation in hypertrophic cardiomyopathy.

    Tanjore RR, Sikindlapuram AD, Calambur N, Thakkar B, Kerkar PG and Nallari P

    Clinical genetics 2006;69;5;434-6

  • [Analysis of MYH7, MYBPC3 and TNNT2 gene mutations in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype].

    Liu WL, Xie WL, Hu DY, Zhu TG, Li YT, Sun YH, Li CL, Li L, Li TC, Bian H, Tong QG, Yang SN, Fan RY and Cui W

    Cardiology Division, People's Hospital, Peking University, Beijing 100044, China.

    Objective: The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM).

    Methods: There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype.

    Results: Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2.

    Conclusions: Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM.

    Zhonghua xin xue guan bing za zhi 2006;34;3;202-7

  • Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.

    Poutanen T, Tikanoja T, Jääskeläinen P, Jokinen E, Silvast A, Laakso M and Kuusisto J

    Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland. tuija.poutanen@koti.tpo.fi

    Objectives: We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children.

    Background: In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations.

    Methods: All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children.

    Results: Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children.

    Conclusions: In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

    American heart journal 2006;151;3;725.e1-725.e9

  • Characteristics of the beta myosin heavy chain gene Ala26Val mutation in a Chinese family with hypertrophic cardiomyopathy.

    Liu SX, Hu SJ, Sun J, Wang J, Wang XT, Jiang Y and Cai J

    Department of Cardiovascular Medicine, The First Affiliated Hospital, College of Medical Science, Zhejiang University, QingChun Road 33, Hangzhou 310003, PR China. s0hu0001@hotmail.com

    Background: Genotype-phenotype studies have suggested that some mutations of genes encoding various components of the cardiac sarcomere cause hypertrophic cardiomyopathy (HCM) and are associated with the prognosis of patients with HCM. The aims of this study were to investigate the gene mutations of exons in the cardiac beta myosin heavy chain (MYH7) gene, the troponin T (TNNT2) gene, and the brain natriuretic peptide (BNP) gene, as well as to assess the effect of these mutations on the clinical features of Chinese patients with HCM.

    Methods: Five unrelated Chinese families with HCM were studied. Exons 3 and 18 in the MYH7 gene, exon 9 in the TNNT2 gene, and all three exons in the BNP gene were screened with the polymerase chain reaction (PCR) for genomic DNA amplification. Further study included purification of PCR products and direct sequencing of PCR fragments by fluorescent end labeling.

    Results: A C-to-T transition in codon 26 of exon 3 in the MYH7 gene was found in one family (including four patients and five carriers), resulting in an amino acid substitution of valine (Val) for alanine (Ala). The Ala26Val mutation was of incomplete dominance (penetrance 44%). This mutation was not seen in the other four families or in the control group. Moreover, the association between the gene mutations of exon 18 in MYH7, of exon 9 of TNNT2, and of all three exons in BNP and HCM was not found in the populations we studied.

    Conclusions: The missense mutation Ala26Val found in this one Chinese family was associated with a mild phenotype of HCM. The genetic and phenotypic heterogeneity of HCM exists in the Chinese population. It suggests that genetic and environmental factors may be involved in the pathogenesis of HCM.

    European journal of internal medicine 2005;16;5;328-33

  • Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

    Perrot A, Schmidt-Traub H, Hoffmann B, Prager M, Bit-Avragim N, Rudenko RI, Usupbaeva DA, Kabaeva Z, Imanov B, Mirrakhimov MM, Dietz R, Wycisk A, Tendera M, Gessner R and Osterziel KJ

    Kardiologie am Campus Buch und Virchow-Klinikum, Charité-Universitätsmedizin Berlin und Max-Delbrück-Centrum für Molekulare Medizin, Wiltbergstrasse 50, 13125 Berlin, Germany. perrot@fvk-berlin.de

    Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol. The DNA of the patients was systematically analyzed in the whole coding region of the MYH7 gene using PCR, single-strand conformation polymorphism analysis, and automated sequencing. Eleven different missense mutations (including seven novel ones) in 11 unrelated patients were identified, showing a mutation frequency of 7.5% in the study population. We further examined the families of five patients (three of German, one of Polish, and one of Kyrgyz origin) with 32 individuals in total. We observed a clear, age-dependent penetrance with onset of disease symptoms in the fourth decade of life. Genotype-phenotype correlations were different for each mutation, whereas the majority was associated with an intermediate/malign phenotype. In conclusion, we report a systematic molecular screening of the complete MYH7 gene in a large group of consecutive HCM patients, leading to a genetic diagnosis in 38 individuals. Information about the genotype in an individual from one family could be very useful for the clinician, especially when dealing with healthy relatives in doubt of their risk about developing HCM. The increasing application of genetic screening and the increasing knowledge about genotype-phenotype correlations will hopefully lead to an improved clinical management of HCM patients.

    Journal of molecular medicine (Berlin, Germany) 2005;83;6;468-77

  • Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease.

    Yu B, Sawyer NA, Caramins M, Yuan ZG, Saunderson RB, Pamphlett R, Richmond DR, Jeremy RW and Trent RJ

    Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital and Central Clinical School, The University of Sydney, Missenden Road, Camperdown, NSW 2050, Australia. bingy@med.usyd.edu.au

    Aims: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) as a high throughput tool in: (1) DNA mutation detection in familial hypertrophic cardiomyopathy (FHC), and (2) single nucleotide polymorphism (SNP) discovery and validation in sporadic motor neurone disease (MND).

    Methods: The coding sequence and intron-exon boundaries of the cardiac beta myosin heavy chain gene (MYH7) were screened by DHPLC for mutation identification in 150 unrelated patients diagnosed with FHC. One hundred and forty patients with sporadic MND were genotyped for the A67T SNP in the poliovirus receptor gene. All DHPLC positive signals were confirmed by conventional methods.

    Results: Mutation screening of MYH7 covered 10 kb with a total of 5700 amplicons, and more than 6750 DHPLC injections were completed within 35 days. The causative mutation was identified in 14% of FHC cases, including seven novel missense mutations (L227V, E328G, K351E, V411I, M435T, E894G, and E927K). Genotyping of the A67T SNP was performed at two different temperatures both in MND cases and 280 controls. This coding SNP was found more frequently in MND cases (13.6%) than in controls (6.8%). Furthermore, 19 and two SNPs were identified in MYH7 and the poliovirus receptor gene, respectively, during DHPLC screening.

    Conclusions: DHPLC is a high throughput, sensitive, specific, and robust platform for the detection of DNA variants, such as disease causing mutations or SNPs. It enables rapid and accurate screening of large genomic regions.

    Journal of clinical pathology 2005;58;5;479-85

  • High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.

    Tian H, Emrich CA, Scherer JR, Mathies RA, Andersen PS, Larsen LA and Christiansen M

    Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.

    A high-density 384-lane microfabricated capillary array electrophoresis device is evaluated for high-throughput single-strand conformation polymorphism (SSCP) analysis. A delayed back bias direct electrokinetic injection scheme is used to provide better than 10-bp resolution with an 8.0-cm effective separation length. Separation of a HaeIII digest of PhiX174 yielded theoretical plate numbers of 4.0 x 10(6). Using 5% PDMA containing 10% glycerol and 15% urea, 21 single-nucleotide polymorphisms (SNPs) from HFE, MYL2, MYL3, and MYH7 genes associated with hereditary hemochromatosis (HHC) and hereditary hypertrophic cardiomyopathy (HCM) are discriminated at two running temperatures (25 degrees C and 40 degrees C), providing 100% sensitivity. The data in this study demonstrate that the 384-lane microCAE device provides the resolution and detection sensitivity required for SSCP analysis, showing its potential for ultrahigh-throughput mutation detection.

    Funded by: NHGRI NIH HHS: HG 01399

    Electrophoresis 2005;26;9;1834-42

  • Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

    Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N and Komajda M

    INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France. villard@chups.jussieu.fr

    Aims: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.

    A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).

    Conclusion: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.

    European heart journal 2005;26;8;794-803

  • Sarcomeric genotyping in hypertrophic cardiomyopathy.

    Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ and Ackerman MJ

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.

    Objective: To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

    Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

    Results: The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.

    Conclusions: Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

    Mayo Clinic proceedings 2005;80;4;463-9

  • Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.

    Alpert NR, Mohiddin SA, Tripodi D, Jacobson-Hatzell J, Vaughn-Whitley K, Brosseau C, Warshaw DM and Fananapazir L

    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA.

    Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding beta-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V(actin)) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V(actin) was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V(actin) for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V(actin) may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.

    Funded by: NHLBI NIH HHS: P01-HL-59408

    American journal of physiology. Heart and circulatory physiology 2005;288;3;H1097-102

  • Myosin storage myopathy: slow skeletal myosin (MYH7) mutation in two isolated cases.

    Laing NG, Ceuterick-de Groote C, Dye DE, Liyanage K, Duff RM, Dubois B, Robberecht W, Sciot R, Martin JJ and Goebel HH

    Centre for Neuromuscular and Neurologic Disorders, Australian Neuromuscular Research Institute and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Australia. nlaing@cyllene.uwa.edu.au

    Myosin storage myopathy is a congenital myopathy characterized by subsarcolemmal hyaline bodies in type 1 muscle fibers, which are ATPase positive and thus contain myosin. Mutations recently were identified in the type 1 muscle fiber myosin gene (MYH7) in Swedish and Saudi families with myosin storage myopathy. The authors have identified the arginine 1845 tryptophan mutation found in the Swedish families in two isolated Belgian cases, indicating a critical role for myosin residue arginine 1845.

    Neurology 2005;64;3;527-9

  • One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region.

    Hougs L, Havndrup O, Bundgaard H, Køber L, Vuust J, Larsen LA, Christiansen M and Andersen PS

    Department of Clinical Biochemistry, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark.

    Familial hypertrophic cardiomyopathy (FHC) is, in most cases, a disease of the sarcomere, caused by a mutation in one of 10 known sarcomere disease genes. More than 266 mutations have been identified since 1989. The FHC disease gene first characterized MYH7, encodes the cardiac beta-myosin heavy chain, and contains more than 115 of these mutations. However, in most studies, only the region encoding the globular head and the hinge region of the mature cardiac beta-myosin heavy chain have been investigated. Furthermore, most studies carries out screening for mutations in the most prevalent disease genes, and discontinues screening when an apparent disease-associated mutation has been identified. The aim of the present study was to screen for mutations in the rod region of the MYH7 gene in all probands of the cohort, regardless of the known genetic status of the proband. Three disease-causing mutations were identified in the rod region in four probands using capillary electrophoresis single-strand conformation polymorphism as a screening method. All mutations were novel: N1327K, R1712W, and E1753K. Two of the probands had already been shown to carry other FHC-associated mutations. In conclusion, we show that in the Danish cohort we find one third of all MYH7 mutations in the rod-encoding region and we find that two of the patients carrying these mutations also carry mutations in other FHC disease genes stressing the need for a complete screening of all known disease genes in FHC-patients.

    European journal of human genetics : EJHG 2005;13;2;161-5

  • Mutations profile in Chinese patients with hypertrophic cardiomyopathy.

    Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J and Hui R

    Sino-German Laboratory for Molecular Medicine, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

    Background: There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China, but the genetic basis is presently unknown.

    Methods: We investigated 100 independent patients with HCM (proband 51, sporadic 49) by sequencing the three most frequent HCM-causing genes (MYH7, MYBPC3, TNNT2).

    Results: Thirty-four patients (34%) carried 25 types of mutations in the selected genes, most (14/25) were newly identified. MYH7 and MYBPC3 accounted for 41% and 18% of the familial HCM, respectively. TNNT2 mutations only caused 2% of the familial HCM. These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM. MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations. The patients carrying R663C, Q734P, E930K in MYH7 and R130C in TNNT2 expressed malignant phenotype. R403Q in MYH7, the most common hot and malignant mutation in Caucasians, was not identified in Chinese.

    Conclusion: We confirmed the diversity of mutation profile in different populations and suggest that a global registry of HCM mutations and their phenotypes is necessary to correlate genotype with phenotype.

    Clinica chimica acta; international journal of clinical chemistry 2005;351;1-2;209-16

  • [The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

    Seleznev DM, Gabrusenko SA, Parfenova EV, Naumov VG, Stambol'skiĭ DV and Tkachuk VA

    One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands). DHPLC was used with subsequent sequencing of DNA fragments. Genetic defects of beta-myosin heavy chain were found more than in every 10-th patient. These defects were represented by 13 mutations (Ala729Pro mutation was found twice). Phenotypes of majority of known mutations in Russian population did not differ substantially from their phenotypes in other populations. Six mutations had not been previously described; most of them were associated with especially severe clinical and hemodynamic signs and relatively unfavorable course of the disease. Thus beta-myosin heavy chain gene mutation play important role in etiology of HCMP in patients in Russia.

    Kardiologiia 2005;45;4;15-20

  • [Mutations in beta myosin heavy chain gene: two mutations in Chinese with familial hypertrophic cardiomyopathy and the correlation between the genotype and phenotype].

    Xie WL, Liu WL, Hu DY, Cui W, Zhu TG, Li CL, Sun YH, Li L, Li TC, Bian H and Tong QG

    Department of Cardiology, Second Hospital, Peking University, Beijing 100044, China.

    Objective: To study the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype.

    Methods: Samples of peripheral blood were collected from five Chinese patients with HCM in whose families at least 2 HCM patients existed. The exon in the functional regions of the beta myosin heavy chain gene (beta-MHC) were amplified with PCR and the products were sequenced. The relation between the genotype and phenotype was analyzed.

    Results: Two mutations were first identified. Eighty controls were normal in the genetic test.

    Conclusion: beta-MHC may be the main disease-causing gene. Two mutations have different phenotypes. In one family, the identical mutation has different phenotypes and prognoses. The heterogeneity of phenotype suggests that multiple factors be involved in the pathogenesis.

    Zhonghua yi xue za zhi 2004;84;19;1610-3

  • Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).

    Meredith C, Herrmann R, Parry C, Liyanage K, Dye DE, Durling HJ, Duff RM, Beckman K, de Visser M, van der Graaff MM, Hedera P, Fink JK, Petty EM, Lamont P, Fabian V, Bridges L, Voit T, Mastaglia FL and Laing NG

    Centre for Human Genetics, Edith Cowan University, Perth, Australia.

    We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.

    Funded by: NINDS NIH HHS: K08 NS042743, K08NS42743, R01NS33645, R01NS36177, R01NS38713

    American journal of human genetics 2004;75;4;703-8

  • Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

    Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ and Ackerman MJ

    Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    Objectives: We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).

    Background: Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.

    Methods: Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.

    Results: Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).

    Conclusions: In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

    Funded by: NICHD NIH HHS: HD42569

    Journal of the American College of Cardiology 2004;44;3;602-10

  • Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy.

    Bohlega S, Abu-Amero SN, Wakil SM, Carroll P, Al-Amr R, Lach B, Al-Sayed Y, Cupler EJ and Meyer BF

    Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    Objective: To identify the gene and specific mutation underlying hyaline body myopathy in the family studied.

    Methods: A microsatellite-based whole genome scan was performed. Linkage analysis assumed autosomal dominant inheritance and equal allele frequencies. A candidate gene approach within the linked interval and direct sequencing were used for mutation detection.

    Results: Initial analysis indicated a maximum lod score of 3.01 at D14S1280. High-density mapping surrounding the linked locus was performed. Multipoint analysis showed that the linked region with a maximum lod score of 3.01 extended from D14S742 to D14S608 with a peak non-parametric linkage (NPL) score of 3.75 at D14S608. The myosin heavy chain genes MYH6 and MYH7 map to the region between D14S742 and D14S1280. Sequence analysis of the coding regions of MYH7 revealed an A-->T transversion at nucleotide position 25596 (M57965) resulting in a histidine-to-leucine amino acid change at residue 1904 (H1904L).

    Conclusion: Pathogenicity of the MYH7 H1904L mutation most likely results from disruption of myosin heavy chain assembly or stability of the sarcomeric protein. The MYH7 tail domain mutation results in an inclusion body myopathy with an apparent absence of hypertrophic cardiomyopathy usually associated with mutations of this gene.

    Neurology 2004;62;9;1518-21

  • Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties.

    Keller DI, Coirault C, Rau T, Cheav T, Weyand M, Amann K, Lecarpentier Y, Richard P, Eschenhagen T and Carrier L

    INSERM U582, Institut de Myologie, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtrière, 47, Bld de l'Hôpital, 75651 Paris cedex 13, France.

    Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.

    Journal of molecular and cellular cardiology 2004;36;3;355-62

Pubmed - other

  • Ca2+-independent positive molecular inotropy for failing rabbit and human cardiac muscle by alpha-myosin motor gene transfer.

    Herron TJ, Devaney E, Mundada L, Arden E, Day S, Guerrero-Serna G, Turner I, Westfall M and Metzger JM

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    Current inotropic therapies used to increase cardiac contractility of the failing heart center on increasing the amount of calcium available for contraction, but their long-term use is associated with increased mortality due to fatal arrhythmias. Thus, there is a need to develop and explore novel inotropic therapies that can act via calcium-independent mechanisms. The purpose of this study was to determine whether fast alpha-myosin molecular motor gene transfer can confer calcium-independent positive inotropy in slow beta-myosin-dominant rabbit and human failing ventricular myocytes. To this end, we generated a recombinant adenovirus (AdMYH6) to deliver the full-length human alpha-myosin gene to adult rabbit and human cardiac myocytes in vitro. Fast alpha-myosin motor expression was determined by Western blotting and immunocytochemical analysis and confocal imaging. In experiments using electrically stimulated myocytes from ischemic failing hearts, AdMYH6 increased the contractile amplitude of failing human [23.9+/-7.8 nm (n=10) vs. AdMYH6 amplitude 78.4+/-16.5 nm (n=6)] and rabbit myocytes. The intracellular calcium transient amplitude was not altered. Control experiments included the use of a green fluorescent protein or a beta-myosin heavy chain adenovirus. Our data provide evidence for a novel form of calcium-independent positive inotropy in failing cardiac myocytes by fast alpha-myosin motor protein gene transfer.

    Funded by: NHLBI NIH HHS: F32 HL080880, L30 HL082192

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2010;24;2;415-24

  • Several common variants modulate heart rate, PR interval and QRS duration.

    Holm H, Gudbjartsson DF, Arnar DO, Thorleifsson G, Thorgeirsson G, Stefansdottir H, Gudjonsson SA, Jonasdottir A, Mathiesen EB, Njølstad I, Nyrnes A, Wilsgaard T, Hald EM, Hveem K, Stoltenberg C, Løchen ML, Kong A, Thorsteinsdottir U and Stefansson K

    deCODE genetics, Reykjavik, Iceland. hilma.holm@decode.is

    Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in approximately 10,000 individuals and followed up the top signals in an additional approximately 10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 x 10(-7)). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 x 10(-5) and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval.

    Nature genetics 2010;42;2;117-22

  • Long single alpha-helical tail domains bridge the gap between structure and function of myosin VI.

    Spink BJ, Sivaramakrishnan S, Lipfert J, Doniach S and Spudich JA

    Department of Biochemistry, Stanford University, 279 Campus Drive, Stanford, California 94305, USA.

    Myosin VI has challenged the lever arm hypothesis of myosin movement because of its ability to take approximately 36-nm steps along actin with a canonical lever arm that seems to be too short to allow such large steps. Here we demonstrate that the large step of dimeric myosin VI is primarily made possible by a medial tail in each monomer that forms a rare single alpha-helix of approximately 10 nm, which is anchored to the calmodulin-bound IQ domain by a globular proximal tail. With the medial tail contributing to the approximately 36-nm step, rather than dimerizing as previously proposed, we show that the cargo binding domain is the dimerization interface. Furthermore, the cargo binding domain seems to be folded back in the presence of the catalytic head, constituting a potential regulatory mechanism that inhibits dimerization.

    Funded by: NIGMS NIH HHS: GM33289, P01 GM066275, P01 GM066275-01A10006, P01 GM066275-020006, P01 GM066275-030006, P01 GM066275-040006, P01 GM066275-050006, R01 GM033289, R01 GM033289-16, R01 GM033289-17, R01 GM033289-18, R01 GM033289-19, R01 GM033289-20, R01 GM033289-21, R01 GM033289-22, R01 GM033289-23, R01 GM033289-24, R01 GM033289-25, T32 GM008294, T32 GM008294-11, T32 GM008294-12, T32 GM008294-13, T32 GM008294-14, T32 GM008294-15, T32 GM008294-16, T32 GM008294-17, T32 GM008294-18, T32 GM008294-19, U54 GM072970

    Nature structural & molecular biology 2008;15;6;591-7

  • Toward a confocal subcellular atlas of the human proteome.

    Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M and Andersson-Svahn H

    Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, SE-106 91 Stockholm, Sweden.

    Information on protein localization on the subcellular level is important to map and characterize the proteome and to better understand cellular functions of proteins. Here we report on a pilot study of 466 proteins in three human cell lines aimed to allow large scale confocal microscopy analysis using protein-specific antibodies. Approximately 3000 high resolution images were generated, and more than 80% of the analyzed proteins could be classified in one or multiple subcellular compartment(s). The localizations of the proteins showed, in many cases, good agreement with the Gene Ontology localization prediction model. This is the first large scale antibody-based study to localize proteins into subcellular compartments using antibodies and confocal microscopy. The results suggest that this approach might be a valuable tool in conjunction with predictive models for protein localization.

    Molecular & cellular proteomics : MCP 2008;7;3;499-508

  • Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

    Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T and Sugano S

    Life Science Research Laboratory, Central Research Laboratory, Hitachi, Ltd., Kokubunji, Tokyo, 185-8601, Japan.

    By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.

    Genome research 2006;16;1;55-65

  • Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy.

    Carniel E, Taylor MR, Sinagra G, Di Lenarda A, Ku L, Fain PR, Boucek MM, Cavanaugh J, Miocic S, Slavov D, Graw SL, Feiger J, Zhu XZ, Dao D, Ferguson DA, Bristow MR and Mestroni L

    Familial Cardiomyopathy Registry Research Group, USA.

    Background: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM.

    A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for alphaMyHC gene (MYH6) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure.

    Conclusions: This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.

    Funded by: NHLBI NIH HHS: 1R01 HL69071-01, 5K23 HL67915-02

    Circulation 2005;112;1;54-9

  • Mutation in myosin heavy chain 6 causes atrial septal defect.

    Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D and Brook JD

    Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.

    Nature genetics 2005;37;4;423-8

  • Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue.

    Narolska NA, van Loon RB, Boontje NM, Zaremba R, Penas SE, Russell J, Spiegelenberg SR, Huybregts MA, Visser FC, de Jong JW, van der Velden J and Stienen GJ

    Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands. na.narolska@vumc.nl

    Objective: Cardiac energetics and performance depend on the expression level of the fast (alpha-) and slow (beta-) myosin heavy chain (MHC) isoform. In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found. In several cardiac diseases, the slow isoform is upregulated; however, the functional implications of this transition in human myocardium are largely unknown. The aim of this study was to determine the relation between contractile properties and MHC isoform composition in healthy human myocardium using the diversity in atrial tissue.

    Methods: Isometric force production and ATP consumption were measured in chemically skinned atrial trabeculae and ventricular muscle strips, and rate of force redevelopment was studied using single cardiomyocytes. MHC isoform composition was determined by one-dimensional SDS-gel electrophoresis.

    Results: Force development in ventricular tissue was about 5-fold more economical, but nine times slower, than in atrial tissue. Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment.

    Conclusion: These results clearly indicate that even a minor shift in MHC isoform expression has considerable impact on cardiac performance in human tissue.

    Cardiovascular research 2005;65;1;221-9

  • Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium.

    Narolska NA, Eiras S, van Loon RB, Boontje NM, Zaremba R, Spiegelen Berg SR, Stooker W, Huybregts MA, Visser FC, van der Velden J and Stienen GJ

    Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands. na.narolska@vumc.nl

    Changes in myosin heavy chain (MHC) isoform expression and protein composition occur during cardiac disease and it has been suggested that even a minor shift in MHC composition may exert a considerable effect on myocardial energetics and performance. Here an overview is provided of the cellular basis of the energy utilisation in cardiac tissue and novel data are presented concerning the economy of myocardial contraction in diseased atrial and ventricular human myocardium. ATP utilisation and force development were measured at various Ca(2+) concentrations during isometric contraction in chemically skinned atrial trabeculae from patients in sinus rhythm (SR) or with chronic atrial fibrillation (AF) and in ventricular muscle strips from non-failing donor or end-stage failing hearts. Contractile protein composition was analysed by one-dimensional gel electrophoresis. Atrial fibrillation was accompanied by a significant shift from the fast alpha-MHC isoform to the slow beta-MHC isoform, whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform. Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure.

    Journal of muscle research and cell motility 2005;26;1;39-48

  • Single-stranded DNA-binding proteins PURalpha and PURbeta bind to a purine-rich negative regulatory element of the alpha-myosin heavy chain gene and control transcriptional and translational regulation of the gene expression. Implications in the repression of alpha-myosin heavy chain during heart failure.

    Gupta M, Sueblinvong V, Raman J, Jeevanandam V and Gupta MP

    Hope Children's Hospital, University of Illinois, Chicago, Illinois 60612, USA.

    The alpha-myosin heavy chain is a principal molecule of the thick filament of the sarcomere, expressed primarily in cardiac myocytes. The mechanism for its cardiac-restricted expression is not yet fully understood. We previously identified a purine-rich negative regulatory (PNR) element in the first intron of the gene, which is essential for its cardiac-specific expression (Gupta, M., Zak, R., Libermann, T. A., and Gupta, M. P. (1998) Mol. Cell. Biol. 18, 7243-7258). In this study we cloned and characterized muscle and non-muscle factors that bind to this element. We show that two single-stranded DNA-binding proteins of the PUR family, PURalpha and PURbeta, which are derived from cardiac myocytes, bind to the plus strand of the PNR element. In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. However, from HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells. We also show that PUR proteins are capable of binding to alpha-MHC mRNA and attenuate its translational efficiency. Furthermore, we show robust expression of PUR proteins in failing hearts where alpha-MHC mRNA levels are suppressed. Together, these results reveal that (i) PUR proteins participate in transcriptional as well as translational regulation of alpha-MHC expression in cardiac myocytes and (ii) ERP may be involved in cardiac-restricted expression of the alpha-MHC gene by preventing its expression in non-muscle cells.

    Funded by: NHLBI NIH HHS: R0-1 HL68083

    The Journal of biological chemistry 2003;278;45;44935-48

  • Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.

    Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG and Seidman CE

    Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

    Background: Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown.

    Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm, systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63+/-42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and alpha-cardiac myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac myosin binding protein-C Arg326Gln) also occurred in a healthy adult.

    Conclusions: Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in beta-cardiac myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for > 45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.

    Circulation 2002;105;4;446-51

  • Calcium not strain regulates localization of alpha-myosin heavy chain mRNA in oriented cardiac myocytes.

    Heidkamp MC and Russell B

    Department of Physiology, and Biophysics (M/C 901), College of Medicine, University of Illinois at Chicago, 60612-7342, USA.

    Our aim was to test a hypothesis that localization of the alpha-myosin heavy chain (alpha-MyHC) mRNA in oriented neonatal rat cardiomyocytes is regulated either by calcium, or by mechanical strain, or by both. Myocytes, grown on collagen aligned on stretchable silicone membranes, were elongated and had an increased length to width ratio (L/W) compared with randomly oriented myocytes grown on conventional substrata. Oriented cells were stretched by 10% in the longitudinal direction, in the transverse direction or passively unloaded for 6 h. As expected, shape changes followed these mechanical deformations. In situ hybridization was used to determine the localization of alpha-MyHC mRNA by quantitative analysis of optical density under various mechanical perturbations in myocytes that were either spontaneously beating or treated with verapamil (10 mM) to block influx of calcium. Unstretched, longitudinally stretched, and cells stretched transversely all had mRNA dispersed to their extremities. Verapamil treatment resulted in a perinuclear pattern of mRNA under all three mechanical perturbations. Additionally, mRNA distribution was examined in myocytes that were passively unloaded in the presence and absence of verapamil. Unloading myocytes with intact calcium cycling does not result in a perinuclear accumulation of mRNA. These data suggest that calcium is essential for alpha-MyHC mRNA distribution throughout the cell whereas stretch and alignment affect myocyte shape but have little effect on mRNA localization.

    Funded by: NHLBI NIH HHS: HL-40880, HL-62426

    Cell and tissue research 2001;305;1;121-7

  • Myosin heavy chain gene expression in human heart failure.

    Nakao K, Minobe W, Roden R, Bristow MR and Leinwand LA

    Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder 80309-0347, USA.

    Two isoforms of myosin heavy chain (MyHC), alpha and beta, exist in the mammalian ventricular myocardium, and their relative expression is correlated with the contractile velocity of cardiac muscle. Several pathologic stimuli can cause a shift in the MyHC composition of the rodent ventricle from alpha- to beta-MyHC. Given the potential physiological consequences of cardiac MyHC isoform shifts, we determined MyHC gene expression in human heart failure where cardiac contractility is impaired significantly. In this study, we quantitated the relative amounts of alpha- and beta-MyHC mRNA in the left ventricular free walls (LVs) of 14 heart donor candidates with no history of cardiovascular disease or structural cardiovascular abnormalities. This group consisted of seven patients with nonfailing (NF) hearts and seven patients with hearts that exhibited donor heart dysfunction (DHD). These were compared with 19 patients undergoing cardiac transplantation for chronic end-stage heart failure (F). The relative amounts of alpha-MyHC mRNA to total (i.e., alpha + beta) MyHC mRNA in the NF- and DHD-LVs were surprisingly high compared with previous reports (33.3+/-18.9 and 35.4+/-16.5%, respectively), and were significantly higher than those in the F-LVs, regardless of the cause of heart failure (2.2+/-3.5%, P < 0.0001). There was no significant difference in the ratios in NF- and DHD-LVs. Our results demonstrate that a considerable amount of alpha-MyHC mRNA is expressed in the normal heart, and is decreased significantly in chronic end-stage heart failure. If protein and enzymatic activity correlate with mRNA expression, this molecular alteration may be sufficient to explain systolic dysfunction in F-LVs, and therapeutics oriented towards increasing alpha-MyHC gene expression may be feasible.

    Funded by: NHLBI NIH HHS: 5R37 HL-50530-04, HL-48013

    The Journal of clinical investigation 1997;100;9;2362-70

  • Structural organization of the human cardiac alpha-myosin heavy chain gene (MYH6).

    Epp TA, Dixon IM, Wang HY, Sole MJ and Liew CC

    Department of Clinical Biochemistry, Toronto Hospital, University of Toronto, Ontario, Canada.

    The human myocardium expresses two cardiac myosin heavy chain (MyHC) isoforms, alpha and beta, that exist in tandem array on chromosome 14q12. We have previously sequenced the entire human cardiac beta-MyHC gene and now report the complete nucleotide sequence of the human cardiac alpha-MyHC, encompassing 26,159 bp as well as the entire 4484-bp 5'-flanking intergenic region. The gene (MYH6) consists of 39 exons, 37 of which contain coding information. The 5'-untranslated region is split into 3 exons, with the third exon containing the AUG translation initiation codon. With the exception of the 13th intron of the human cardiac beta-MyHC, which is not present within the alpha-isogene, all exon/intron boundaries are conserved. Conspicuous sequence motifs contained within the alpha-MyHC gene include four Alu repeats, a single (GT)n element, and a homopurine-homopyrimidine tract containing 23 GAA repeating units followed by 10 GAG repeating units. Comparison of the encoded amino acid sequence with a previously reported human alpha-MyHC cDNA sequence reveals several potential polymorphisms.

    Genomics 1993;18;3;505-9

  • Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin.

    Shoeman RL, Sachse C, Höner B, Mothes E, Kaufmann M and Traub P

    Max-Planck-Institut für Zellbiologie, Ladenburg, Federal Republic of Germany.

    HeLa cell actin was cleaved by human immunodeficiency virus type 1 protease when in its soluble, globular form (G-actin). No cleavage of the polymerized, filamentous form of actin (F-actin) was observed when examined by denaturing gel electrophoresis; however, electron microscopy revealed a low level of cleavage of F-actin. Immunoblotting of mouse skeletal and human pectoral muscle myofibrils treated in vitro with human immunodeficiency virus type 1 protease showed that myosin heavy chain, desmin, tropomyosin, and a fraction of the actin were all cleaved. Electron microscopy of these myofibrils demonstrated changes consistent with cleavage of these proteins: Z-lines were rapidly lost, the length of the A bands was shortened, and the thick filaments (myosin filaments) were often laterally frayed such that the structures disintegrated. Nonmuscle myosin heavy chains were also cleaved by this enzyme in vitro. These data demonstrate that this protease can cause alterations in muscle cell ultrastructure in vitro that may be of clinical relevance in infected individuals.

    The American journal of pathology 1993;142;1;221-30

  • Complete sequence of human cardiac alpha-myosin heavy chain gene and amino acid comparison to other myosins based on structural and functional differences.

    Matsuoka R, Beisel KW, Furutani M, Arai S and Takao A

    Department of Pediatric Cardiology, Tokyo Women's Medical College, Japan.

    We have obtained the 5820 nucleotide sequence encoding all 1939 amino acids of the human cardiac alpha-myosin heavy chain (alpha-MHC), as established by dideoxy sequencing of cloned cDNA, genomic DNA and polymerase chain reaction (PCR) amplification products. This sequence represents overlapping fragments of the entire coding sequence. Amino acid sequence comparison of the human cardiac alpha-MHC with the published human cardiac beta-MHC have demonstrated that there are, at least, 7 isoform-specific divergent regions, including functionally important binding protein-related sites such as ATP, actin and myosin light chain. It has been reported that in the rat, there are 8 isoform-specific divergent regions. The 7th divergent area (residue area 1633-1657, which is thought to mediate thick filament formation) in the light meromyosin region in the rat is not apparent in the human. The amino acid compositions of cardiac alpha- and beta-MHCs in the human and the rat, and human embryonic skeletal muscle and chicken gizzard smooth muscles were compared. Amino acid sequences in cardiac alpha- and beta-MHCs in the human and the rat are well conserved. In the head portion, the amino acid composition divergence of human cardiac alpha-MHC is ranked between rat cardiac alpha-MHC and human cardiac beta- or rat cardiac beta-MHC; human skeletal muscle MHC is the most divergent of the myosin isoform examined. These data predict that human cardiac alpha-MHC may have undergone evolutionary changes toward obtaining the biochemical and physiological properties of cardiac beta-MHC.

    American journal of medical genetics 1991;41;4;537-47

  • Determination of the 5' exon structure of the human cardiac alpha-myosin heavy chain gene.

    Brand NJ, Dabhade N, Yacoub M and Barton PJ

    Department of Cardiothoracic Surgery, National Heart and Lung Institute, London, U.K.

    We have deduced the exon structure of the 5' untranslated region of the human cardiac alpha-myosin heavy chain gene by cloning a cDNA for this region using the polymerase chain reaction. Comparison of the cDNA and genomic DNA sequences demonstrates that the 5' non-coding region of the alpha-myosin heavy chain gene is interrupted by two introns of 645 and 337 nucleotides. Secondly we have identified the transcriptional start-site by primer extension, corroborating the previous putative assignment for the alpha-myosin heavy chain promoter based on comparisons between the rat and human genes.

    Biochemical and biophysical research communications 1991;179;3;1255-8

  • Nucleotide sequence of chimpanzee Fc and hinge regions.

    Ehrlich PH, Moustafa ZA and Ostberg L

    Sandoz Research Institute, Sandoz Pharmaceuticals Corp., E. Hanover, NJ 07936.

    The nucleotide sequence of the Fc and hinge regions of a chimpanzee monoclonal antibody has been determined. Most of the sequence is similar to the human IgG1 sequence. However, the chimpanzee hinge regions differs from the human hinge region in six of 48 nucleotides, which leads to three amino acid substitutions. Two of the amino acid changes are not conservative and may lead to differences in flexibility of the hinge. The chimp hinge sequence seems to be a combination of the human IgG1 hinge and the hinge sequence of a human IgG pseudogene. The implications of this difference for the evolution of human IgG subgroup is discussed. Despite differences in the hinge regions, the chimpanzee monoclonal antibody differs from the most closely related human IgG1 allotype only slightly more than the two most distantly related human allotypes differ from each other.

    Molecular immunology 1991;28;4-5;319-22

  • A molecular basis for familial hypertrophic cardiomyopathy: an alpha/beta cardiac myosin heavy chain hybrid gene.

    Tanigawa G, Jarcho JA, Kass S, Solomon SD, Vosberg HP, Seidman JG and Seidman CE

    Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115.

    An alpha/beta cardiac myosin heavy chain (MHC) hybrid gene is coinherited with familial hypertrophic cardiomyopathy (FHC) in one kindred. FHC is a disease of the heart muscle characterized by a thickening of the left ventricular wall with myocyte and myofibrillar disarray that is inherited as an autosomal dominant trait. We demonstrate here and in the accompanying article that the cardiac MHC genes, which encode integral myofibrillar components, are mutated in all affected individuals from two unrelated families with FHC. In one kindred, an unequal crossover event during meiosis may have produced the alpha/beta cardiac MHC hybrid gene that is present in affected individuals. We conclude that mutations in the cardiac MHC genes can cause FHC.

    Funded by: NHLBI NIH HHS: 1F32-HL08096, HL41474, HL42467; ...

    Cell 1990;62;5;991-8

  • A locus for familial hypertrophic cardiomyopathy is closely linked to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on chromosome 14 at q11-q12.

    Solomon SD, Geisterfer-Lowrance AA, Vosberg HP, Hiller G, Jarcho JA, Morton CC, McBride WO, Mitchell AL, Bale AE, McKenna WJ et al.

    Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

    We report that a gene responsible for familial hypertrophic cardiomyopathy (HC) is closely linked to the cardiac alpha and beta myosin heavy chain (MHC) genes on chromosome 14q11. We have recently shown that probe CRI-L436, derived from the anonymous DNA locus D14S26, detects a polymorphic restriction fragment that segregates with familial HC in affected members of a large Canadian family. Using chromosomal in situ hybridization, we have mapped CRI-L436 to chromosome 14 at q11-q12. Because the cardiac MHC genes also map to this chromosomal band, we have determined the genetic distances between the cardiac beta MHC gene, D14S26, and the familial HC locus. Data presented here show that these three loci are linked within 5 centimorgans on chromosome 14 at q11-q12. The possibility that defects in either the cardiac alpha or beta MHC genes are responsible for familial HC is discussed.

    Funded by: NHLBI NIH HHS: 1F32-HL08096, HL42467, R29-HL41474

    American journal of human genetics 1990;47;3;389-94

  • Characterization of human cardiac myosin heavy chain genes.

    Yamauchi-Takihara K, Sole MJ, Liew J, Ing D and Liew CC

    Department of Medicine, Max Bell Research Center, Toronto General Hospital, University of Toronto, ON, Canada.

    We have isolated and analyzed the structure of the genes coding for the alpha and beta forms of the human cardiac myosin heavy chain (MYHC). Detailed analysis of four overlapping MYHC genomic clones shows that the alpha-MYHC and beta-MYHC genes constitute a total length of 51 kilobases and are tandemly linked. The beta-MYHC-encoding gene, predominantly expressed in the normal human ventricle and also in slow-twitch skeletal muscle, is located 4.5 kilobases upstream of the alpha-MYHC-encoding gene, which is predominantly expressed in normal human atrium. We have determined the nucleotide sequences of the beta form of the MYHC gene, which is 100% homologous to the cardiac MYHC cDNA clone (pHMC3). It is unlikely that the divergence of a few nucleotide sequences from the cardiac beta-MYHC cDNA clone (pHMC3) reported in a MYHC cDNA clone (pSMHCZ) from skeletal muscle is due to a splicing mechanism. This finding suggests that the same beta form of the cardiac MYHC gene is expressed in both ventricular and slow-twitch skeletal muscle. The promoter regions of both alpha- and beta-MYHC genes, as well as the first four coding regions in the respective genes, have also been sequenced. The sequences in the 5'-flanking region of the alpha- and beta-MYHC-encoding genes diverge extensively from one another, suggesting that expression of the alpha- and beta-MYHC genes is independently regulated.

    Proceedings of the National Academy of Sciences of the United States of America 1989;86;10;3504-8

  • Human cardiac myosin heavy chain gene mapped within chromosome region 14q11.2----q13.

    Matsuoka R, Yoshida MC, Kanda N, Kimura M, Ozasa H and Takao A

    Department of Pediatric Cardiology, Heart Institute of Japan, Tokyo.

    Our previous report demonstrated that two human cardiac alpha- and beta-myosin heavy-chains (MHCs) which correspond to MYH6 and MYH7 respectively, according to Human Gene Mapping nomenclature, were mapped to human chromosome 14 and that human cardiac and skeletal MHC genes do not cosegregate. For further analysis, the regional mapping method was used. DNA from 4 human deletion and 3 human duplication cell lines were prepared for southern blotting, hybridized with human cardiac alpha- and beta-MHC DNA probes, and the hybridization intensity relative to 46,XX or 46,XY DNA was estimated. The results showed that two human cardiac MHC genes segregated with the 14cen----q13 region of the long arm of human chromosome 14. In situ hybridization of 3H-labeled human cardiac alpha-MHC probe to normal human metaphase chromosome independently confirmed this result.

    American journal of medical genetics 1989;32;2;279-84

  • Molecular cloning and characterization of human cardiac alpha- and beta-form myosin heavy chain complementary DNA clones. Regulation of expression during development and pressure overload in human atrium.

    Kurabayashi M, Tsuchimochi H, Komuro I, Takaku F and Yazaki Y

    Third Department of Internal Medicine, University of Tokyo, Japan.

    We have constructed and characterized two types of myosin heavy chain (MHC) cDNA clones (pHMHC2, pHMHC5) from a fetal human heart cDNA library. Comparison of the nucleotide and deduced amino acid sequences between pHMHC2 and pHMHC5 shows 95.1 and 96.2% homology, respectively. The carboxyl-terminal peptide and 3'-untranslated (3'-UT) regions are highly divergent and specific for these cDNA clones. By using the synthetic oligonucleotide probes that are complementary to the unique 3'-UT regions of these cDNA clones, we demonstrate that pHMHC2 is exclusively transcribed in the atrium, whereas the mRNA for pHMHC5 is predominantly expressed in the ventricle. This result indicates that pHMHC2 and pHMHC5 code for alpha- and beta-form MHCs, respectively. Furthermore, we show that beta-form MHC mRNA is expressed in adult atrium at a low level but scarcely expressed in fetal atrium. Finally, we demonstrate that MHC isozymic transition in pressure-overloaded atrium is, at least in part, regulated at a pretranslational level.

    The Journal of clinical investigation 1988;82;2;524-31

  • Human cardiac myosin heavy chain genes and their linkage in the genome.

    Saez LJ, Gianola KM, McNally EM, Feghali R, Eddy R, Shows TB and Leinwand LA

    Human myosin heavy chains are encoded by a multigene family consisting of at least 10 members. A gene-specific oligonucleotide has been used to isolate the human beta myosin heavy chain gene from a group of twelve nonoverlapping genomic clones. We have shown that this gene (which is expressed in both cardiac and skeletal muscle) is located 3.6kb upstream of the alpha cardiac myosin gene. We find that DNA sequences located upstream of rat and human alpha cardiac myosin heavy chain genes are very homologous over a 300bp region. Analogous regions of two other myosin genes expressed in different muscles (cardiac and skeletal) show no such homology to each other. While a human skeletal muscle myosin heavy chain gene cluster is located on chromosome 17, we show that the beta and alpha human cardiac myosin heavy chain genes are located on chromosome 14.

    Funded by: NICHD NIH HHS: HD05196; NIGMS NIH HHS: GM20454, GM29090

    Nucleic acids research 1987;15;13;5443-59

Gene lists (2)

Gene List Source Species Name Description Gene count
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.