G2Cdb::Human Disease report

Disease id
D00000236
Name
Hypertrophic cardiomyopathy (familial)
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (7796500) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (7796500) Nonsense (No) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (7848441) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (7959583) Microinsertion (MI) N
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8254035) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8282798) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8343162) Single nucleotide polymorphism (SNP) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8655135) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8825881) Deletion (D) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8944596) Insertion/deletion (I/D) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (9822100) Microinsertion (MI) N
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (9829907) Deletion (D) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (9829907) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (10374350) Repeat polymorphism (RP) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (10521296) Microinsertion (MI) Y
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (11133230) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15483641) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15528230) Polymorphism (P) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (15858117) Microinsertion (MI) Y
G00002430 MYH6
myosin, heavy chain 6, cardiac muscle, alpha
Y (17081393) No mutation found (N) N

References

  • [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

  • 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

  • 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

  • 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

  • Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children.

    Greber-Platzer S, Marx M, Fleischmann C, Suppan C, Dobner M and Wimmer M

    Department of Pediatrics, Division of Pediatric Cardiology, University of Vienna, Währinger Gürtel 18-20, Vienna, A-1090, Austria. Susanne.Greber-Platzer@akh-wien.ac.at

    Hypertrophic cardiomyopathy occurs in two variants, either as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. Different genes coding sarcomeric proteins of the heart have been identified as causing hypertrophic cardiomyopathy. Missense mutations in the cardiac beta-myosin heavy chain gene are found in 30% of all cases of familial hypertrophic cardiomyopathy. We screened the beta-myosin heavy chain gene of children of nine Austrian families with hypertrophic cardiomyopathy (referred to as group A) and of seven children with sporadic hypertrophic cardiomyopathy (referred to as group B). We were able to find two previously described (V606M, R453C) and two unknown missense mutations (V406M, R663H) in group A. Additionally, in two children of group B we could identify one already known missense mutation, R249Q as well as one previously unknown missense mutation, M877K. The genetically affected children of group A developed no or only mild clinical symptoms, whereas the children of group B with genetically confirmed sporadic hypertrophic cardiomyopathy showed manifest left ventricular hypertrophy and clinical symptoms including chest pain and dyspnoea. Clinical symptoms among the adults of group A, suffering from familial hypertrophic cardiomyopathy, varied significantly. We therefore believe V406M to be a more malignant missense mutation, probably linked with sudden death in the affected family, than R663H, which seems to be more benign causing late-onset hypertrophic cardiomyopathy and mild clinical symptoms in the affected family members.

    Journal of molecular and cellular cardiology 2001;33;1;141-8

  • The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events.

    Moolman-Smook JC, De Lange WJ, Bruwer EC, Brink PA and Corfield VA

    US/MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, University of Stellenbosch Medical School, Tygerberg, South Africa.

    Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.

    American journal of human genetics 1999;65;5;1308-20

  • The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population.

    Jääskeläinen P, Soranta M, Miettinen R, Saarinen L, Pihlajamäki J, Silvennoinen K, Tikanoja T, Laakso M and Kuusisto J

    Department of Medicine, University of Kuopio, Finland.

    Objectives: The aim of the study was to screen 36 unrelated patients with hypertrophic cardiomyopathy (HCM; 16 familial and 20 sporadic cases) from a genetically homogeneous area in eastern Finland for variants in the cardiac beta-myosin heavy chain (beta-MHC) and alpha-tropomyosin (alpha-TM) genes.

    Background: Mutations in the beta-MHC and alpha-TM genes have been reported to be responsible for 30% to 40% and less than 5% of familial HCM cases, respectively. However, most genetic studies have included patients from tertiary care centers and are subject to referral bias.

    Methods: Exons 3-26 and 40 of the beta-MHC gene and the nine exons of the alpha-TM gene were screened with the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method. Linkage analyses between familial HCM locus and two intragenic polymorphic markers (MYO I and MYO II) of the beta-MHC gene were performed in 16 familial HCM kindreds.

    Results: A previously reported Arg719Trp (arginine converted to tryptophan in codon 719) mutation of the beta-MHC gene was found in one proband and two relatives. In addition, a novel Asn696Ser (asparagine converted to serine in codon 696) substitution was found in one HCM patient. No linkage between familial HCM and the beta-MHC gene was observed in 16 familial kindreds. A previously reported Aspl75Asn (aspartic acid converted to asparagine in codon 175) mutation of the alpha-TM gene was found in four probands and 16 relatives. Mutations in the beta-MHC and alpha-TM genes accounted for 6% and 25% familial HCM cases and 3% and 11% of all cases, respectively.

    Conclusions: Our results indicate that the beta-MHC gene is not the predominant gene for HCM in the Finnish population, whereas HCM caused by the Aspl75Asn mutation of the a-TM gene is more common than previously reported.

    Journal of the American College of Cardiology 1998;32;6;1709-16

  • Genetic heterogeneity for familial hypertrophic cardiomyopathy in Chinese: analysis of six Chinese kindreds.

    Ko YL, Teng MS, Tang TK, Chen JJ, Lee YS, Wu CW, Lien WP and Liew CC

    First Cardiovascular Division, Chang Gung Memorial Hospital, Taipei, China.

    Objective: Familial hypertrophic cardiomyopathy (FHCM) is a primary myocardial disease characterized by unexplained ventricular hypertrophy. The application of the techniques of reverse genetics has identified at least five chromosomal loci as the major causes for FHCM in diverse ethnic populations, suggesting substantial genetic heterogeneity for FHCM. Recently, the defective gene loci of two Chinese families with FHCM have been mapped to chromosome 11 and 14q1, respectively. For further understanding of the molecular basis of FHCM in Chinese, we analyzed the linkage between four other Chinese kindreds and DNA markers from chromosome 14q1.

    Methods: Six unrelated Chinese families with FHCM, including two previously reported, were studied. Totally 90 family members were included for analysis. DNA from 80 individuals was extracted and polymerase chain reactions were performed using the primers designed according to the sequences derived from the alpha and beta myosin heavy chain gene. Totally four polymorphisms were studied, including three polymorphic microsatellite sequences and one single strand conformation polymorphism. Genetic linkage analysis were performed using the Linkage program.

    Results: In the six studied families, 39 of the 90 family members were found to be affected diagnosed either by echocardiography or by clinical evaluation. The pattern of inheritance in all six studied families was most consistent with an autosomal dominant trait with a high degree of penetrance. Genetic linkage analysis using polymorphisms on the alpha and beta MHC genes showed a combined maximal lod score of 6.2 for trinucleotide repeat polymorphism AMHC-I 15 at theta = 0.00 for three studied families without recombination. Exclusion of linkage to the chromosome 14q1 location was noted in two of three other families with the maximal lod score of -2 or less.

    Conclusions: These results provide further evidence that FHCM in Chinese is genetically heterogeneous. Chromosome 14q1 locus, probably the beta myosin heavy chain gene, is important as the molecular basis for FHCM in Chinese.

    Chinese medical journal 1998;111;5;416-21

  • Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

    Tesson F, Richard P, Charron P, Mathieu B, Cruaud C, Carrier L, Dubourg O, Lautié N, Desnos M, Millaire A, Isnard R, Hagege AA, Bouhour JB, Bennaceur M, Hainque B, Guicheney P, Schwartz K and Komajda M

    INSERM UR 153, Groupe Hospitalier Pitié-Salpétrière, Paris, France. tesson@infobiogen.fr

    Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease in which one of the most frequently implicated gene is the gene encoding the beta-myosin heavy chain. To date, more than 40 distinct mutations have been found within this gene. In order to progress on the determination of genotype-phenotype relationship, we have screened the beta-myosin heavy chain gene for mutations in 18 probands from unrelated families. We identified the mutation implicated in the disease in four families. Two of them, the Glu930 codon deletion and the Ile263Thr mutation, are reported here for the first time. The two other mutations are the Arg723Cys mutation, that was previously described in a proband as a de novo mutation, and the Arg719Trp mutation. A poor prognosis was associated with the Glu930codon deletion (mean maximal wall thickness (MWT) = 19.5 mm +/- 5) and the Arg719Trp mutation (mean MWT = 15.3 mm +/- 7), whereas a good prognosis was associated with the Arg723Cys mutation (mean MWT = 20.1 mm +/- 7). The combination of clinical and genetic characteristics of each family member suggests that prognosis is related neither to the degree of left ventricular wall thickness nor to a change in the net electrical charge of the protein. Additional family studies are needed to confirm these findings and to contribute to stratify the prognosis according to the mutation involved.

    Human mutation 1998;12;6;385-92

  • A previously undescribed de novo insertion-deletion mutation in the beta myosin heavy chain gene in a kindred with familial hypertrophic cardiomyopathy.

    Cuda G, Perrotti N, Perticone F and Mattioli PL

    Dipartimento di Medicina Sperimentale e Clinica, Università di Reggio Calabria, Catanzaro, Italy.

    A previously undescribed de novo insertion-deletion mutation in the beta cardiac myosin heavy chain gene was found in a kindred with familial hypertrophic cardiomyopathy. In the mutated allele there is an inserted-deleted guanine at nucleotides 8823 and 8850 of the beta myosin heavy chain gene, resulting in a dramatic change of the amino acid sequence (AA 395-404). such a mutation, detected in the proband and in his son but not in the proband's parents, is likely to produce major impairment of myosin function.

    Heart (British Cardiac Society) 1996;76;5;451-2

  • Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg-->Cys mutation in the beta-myosin heavy chain gene: coexistence of sudden death and end-stage heart failure.

    Ko YL, Chen JJ, Tang TK, Cheng JJ, Lin SY, Liou YC, Kuan P, Wu CW, Lien WP and Liew CC

    Department of Internal Medicine, National Taiwan University Hospital, Taipei, Republic of China.

    Recent genotype-phenotype correlation studies in familial hypertrophic cardiomyopathy (FHC) have revealed that some mutations in the beta- myosin heavy chain (BMHC) gene may be associated with a high incidence of sudden death and a poor prognosis. Coexistence of sudden death and end-stage heart failure in several families with FHC has recently being reported; however, the genetic basis of such families has not been clearly demonstrated. A three-generation Chinese familial hypertrophic cardiomyopathy (FHC) family (family HLI) with two cases of end-stage heart failure and three cases of sudden death was analyzed. The average age of death in the affected members in this family was 34 years old. Genetic linkage analysis using polymorphisms in the (alpha- and beta-myosin heavy chain genes revealed that FHC in this family is significantly linked to the BMHC gene without recombinations. Single-strand conformation polymorphism analysis of exons 8, 9 and 13 to 23 in the BMHC gene showed a polymorphic band on exon 14 that is in complete linkage with the disease status in this family. DNA sequencing analysis in the affected members revealed an 453Arg-->Cys mutation in the BMHC gene. To our knowledge this is the first reported mutation of FHC in Chinese. Our data suggest that the 453Arg-->Cys mutation is associated with a malignant clinical course in FHC due not only to sudden death but also to end-stage heart failure.

    Human genetics 1996;97;5;585-90

  • A novel deletion mutation in the beta-myosin heavy chain gene found in Japanese patients with hypertrophic cardiomyopathy.

    Nakajima-Taniguchi C, Matsui H, Eguchi N, Nagata S, Kishimoto T and Yamauchi-Takihara K

    Department of Medicine III, Osaka University Medical School, Japan.

    Mutations in the cardiac beta-myosin heavy chain (MHC) gene of 50 Japanese patients with hypertrophic cardiomyopathy (HCM) were investigated by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. A novel deletion mutation was detected in exon 3 of the cardiac beta-MHC gene in a Japanese family with HCM. Sequencing analysis revealed a three nucleotide deletion at codon 10 leading to a deletion of a glycine residue, which has been conserved in the myosin gene from birds to humans. Because this deletion mutation was not detected in other healthy family members, it was suggested that this 10Gly deletion is the cause of HCM in this family. The same deletion mutation has been found in three other unrelated patients with HCM. This is the first report of a one codon deletion in the beta-MHC gene in patients with HCM.

    Journal of molecular and cellular cardiology 1995;27;12;2607-12

  • A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy.

    Nishi H, Kimura A, Harada H, Koga Y, Adachi K, Matsuyama K, Koyanagi T, Yasunaga S, Imaizumi T, Toshima H et al.

    Third Department of Internal Medicine, Kurume University School of Medicine, Japan.

    Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac beta-myosin-heavy-chain (beta-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac beta-MHC gene, ie, an alpha/beta hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood.

    We analyzed the structure of the cardiac beta-MHC gene from patients with HCM by using polymerase chain reaction-DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families.

    Conclusions: The Arg870His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac beta-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac beta-MHC gene.

    Circulation 1995;91;12;2911-5

  • [Genetic heterogeneity of hypertrophic cardiomyopathy in Japanese].

    Machida M

    Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.

    Familial hypertrophic cardiomyopathy (FHCM) is thought to be caused by missense mutations in cardiac beta-myosin heavy chain (beta-MHC) gene in 30-40% of affected Caucasian individuals. On the other hand, it has been reported that Japanese FHCM is closely linked to DNA marker PALB on chromosome 18q by linkage analysis. Therefore, in order to elucidate the etiological significance of missense mutations in beta-MHC gene in Japanese HCM patients, we have investigated the sequence variation in exon 3 to 25 of beta-MHC gene from 16 multiplex FHCM kindreds and 28 sporadic patients by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method. In this study we demonstrated one missense mutation (codon741: GlyGGG-->ArgAGG) in only one kindred among 16 multiplex Japanese kindreds with FHCM. Two synonymous mutations (codon715: TryTAC-->TryTAT, codon 989: IleATT-->IleATC) are demonstrated in another kindred. The same mutation in codon 989 is also detected in one sporadic patient. Furthermore, we performed linkage study with two DNA markers (F13B on chromosome 1q, D11S916: AMF185yal on chromosome 11p-q) which are recently reported to be linked with FHCM. Three and four families showed statistically negative linkage with F13B and D11S916 (AMF185yal), respectively. These results suggest that several responsible genes for HCM may exist in Japanese and principal responsible gene for Japanese HCM is different from it for Caucasian HCM.

    [Hokkaido igaku zasshi] The Hokkaido journal of medical science 1994;69;4;1024-34

  • A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy.

    Consevage MW, Salada GC, Baylen BG, Ladda RL and Rogan PK

    Department of Pediatrics, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17036.

    Human molecular genetics 1994;3;6;1025-6

  • Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy.

    Anan R, Greve G, Thierfelder L, Watkins H, McKenna WJ, Solomon S, Vecchio C, Shono H, Nakao S, Tanaka H et al.

    Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.

    Three novel beta cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change.

    Funded by: NHLBI NIH HHS: HL-42467, HL-46320, P50-HL-42267

    The Journal of clinical investigation 1994;93;1;280-5

  • Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

    Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Wisnewsky C, Bercovici J, Hengstenberg C, al-Mahdawi S et al.

    Institut National de la Sante et de la Recherche Médicale, U127, Hôpital Lariboisière, Paris, France.

    Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

    The Journal of clinical investigation 1993;92;6;2807-13

  • A missense mutation of cardiac beta-myosin heavy chain gene linked to familial hypertrophic cardiomyopathy in affected Japanese families.

    Harada H, Kimura A, Nishi H, Sasazuki T and Toshima H

    Third Department of Internal Medicine, Kurume University, School of Medicine, Japan.

    A novel missense mutation of the cardiac beta-myosin heavy chain gene was detected in five unrelated Japanese patients and their affected family members with hypertrophic cardiomyopathy (HCM) by using the polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis. Sequencing analysis revealed an A to G transition at codon 778 leading to replacement of the Asp residue, which is adjacent to the interaction sites of myosin heavy chain (MHC) with actin and is a conserved amino acid residue in various MHC across species, to the Gly residue. Linkage study of the mutation and two dinucleotides repeat markers of the cardiac beta-MHC gene in three affected families showed that the mutation was on the same haplotype of the cardiac beta-MHC gene and linked to HCM. These observations strongly suggest that the 778Asp to Gly mutation is the cause of HCM in these affected individuals.

    Biochemical and biophysical research communications 1993;194;2;791-8

Literature (18)

Pubmed - human_disease

  • [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

  • 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

  • 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

  • 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

  • Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children.

    Greber-Platzer S, Marx M, Fleischmann C, Suppan C, Dobner M and Wimmer M

    Department of Pediatrics, Division of Pediatric Cardiology, University of Vienna, Währinger Gürtel 18-20, Vienna, A-1090, Austria. Susanne.Greber-Platzer@akh-wien.ac.at

    Hypertrophic cardiomyopathy occurs in two variants, either as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. Different genes coding sarcomeric proteins of the heart have been identified as causing hypertrophic cardiomyopathy. Missense mutations in the cardiac beta-myosin heavy chain gene are found in 30% of all cases of familial hypertrophic cardiomyopathy. We screened the beta-myosin heavy chain gene of children of nine Austrian families with hypertrophic cardiomyopathy (referred to as group A) and of seven children with sporadic hypertrophic cardiomyopathy (referred to as group B). We were able to find two previously described (V606M, R453C) and two unknown missense mutations (V406M, R663H) in group A. Additionally, in two children of group B we could identify one already known missense mutation, R249Q as well as one previously unknown missense mutation, M877K. The genetically affected children of group A developed no or only mild clinical symptoms, whereas the children of group B with genetically confirmed sporadic hypertrophic cardiomyopathy showed manifest left ventricular hypertrophy and clinical symptoms including chest pain and dyspnoea. Clinical symptoms among the adults of group A, suffering from familial hypertrophic cardiomyopathy, varied significantly. We therefore believe V406M to be a more malignant missense mutation, probably linked with sudden death in the affected family, than R663H, which seems to be more benign causing late-onset hypertrophic cardiomyopathy and mild clinical symptoms in the affected family members.

    Journal of molecular and cellular cardiology 2001;33;1;141-8

  • The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events.

    Moolman-Smook JC, De Lange WJ, Bruwer EC, Brink PA and Corfield VA

    US/MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, University of Stellenbosch Medical School, Tygerberg, South Africa.

    Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.

    American journal of human genetics 1999;65;5;1308-20

  • Genetic heterogeneity for familial hypertrophic cardiomyopathy in Chinese: analysis of six Chinese kindreds.

    Ko YL, Teng MS, Tang TK, Chen JJ, Lee YS, Wu CW, Lien WP and Liew CC

    First Cardiovascular Division, Chang Gung Memorial Hospital, Taipei, China.

    Objective: Familial hypertrophic cardiomyopathy (FHCM) is a primary myocardial disease characterized by unexplained ventricular hypertrophy. The application of the techniques of reverse genetics has identified at least five chromosomal loci as the major causes for FHCM in diverse ethnic populations, suggesting substantial genetic heterogeneity for FHCM. Recently, the defective gene loci of two Chinese families with FHCM have been mapped to chromosome 11 and 14q1, respectively. For further understanding of the molecular basis of FHCM in Chinese, we analyzed the linkage between four other Chinese kindreds and DNA markers from chromosome 14q1.

    Methods: Six unrelated Chinese families with FHCM, including two previously reported, were studied. Totally 90 family members were included for analysis. DNA from 80 individuals was extracted and polymerase chain reactions were performed using the primers designed according to the sequences derived from the alpha and beta myosin heavy chain gene. Totally four polymorphisms were studied, including three polymorphic microsatellite sequences and one single strand conformation polymorphism. Genetic linkage analysis were performed using the Linkage program.

    Results: In the six studied families, 39 of the 90 family members were found to be affected diagnosed either by echocardiography or by clinical evaluation. The pattern of inheritance in all six studied families was most consistent with an autosomal dominant trait with a high degree of penetrance. Genetic linkage analysis using polymorphisms on the alpha and beta MHC genes showed a combined maximal lod score of 6.2 for trinucleotide repeat polymorphism AMHC-I 15 at theta = 0.00 for three studied families without recombination. Exclusion of linkage to the chromosome 14q1 location was noted in two of three other families with the maximal lod score of -2 or less.

    Conclusions: These results provide further evidence that FHCM in Chinese is genetically heterogeneous. Chromosome 14q1 locus, probably the beta myosin heavy chain gene, is important as the molecular basis for FHCM in Chinese.

    Chinese medical journal 1998;111;5;416-21

  • Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

    Tesson F, Richard P, Charron P, Mathieu B, Cruaud C, Carrier L, Dubourg O, Lautié N, Desnos M, Millaire A, Isnard R, Hagege AA, Bouhour JB, Bennaceur M, Hainque B, Guicheney P, Schwartz K and Komajda M

    INSERM UR 153, Groupe Hospitalier Pitié-Salpétrière, Paris, France. tesson@infobiogen.fr

    Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease in which one of the most frequently implicated gene is the gene encoding the beta-myosin heavy chain. To date, more than 40 distinct mutations have been found within this gene. In order to progress on the determination of genotype-phenotype relationship, we have screened the beta-myosin heavy chain gene for mutations in 18 probands from unrelated families. We identified the mutation implicated in the disease in four families. Two of them, the Glu930 codon deletion and the Ile263Thr mutation, are reported here for the first time. The two other mutations are the Arg723Cys mutation, that was previously described in a proband as a de novo mutation, and the Arg719Trp mutation. A poor prognosis was associated with the Glu930codon deletion (mean maximal wall thickness (MWT) = 19.5 mm +/- 5) and the Arg719Trp mutation (mean MWT = 15.3 mm +/- 7), whereas a good prognosis was associated with the Arg723Cys mutation (mean MWT = 20.1 mm +/- 7). The combination of clinical and genetic characteristics of each family member suggests that prognosis is related neither to the degree of left ventricular wall thickness nor to a change in the net electrical charge of the protein. Additional family studies are needed to confirm these findings and to contribute to stratify the prognosis according to the mutation involved.

    Human mutation 1998;12;6;385-92

  • A previously undescribed de novo insertion-deletion mutation in the beta myosin heavy chain gene in a kindred with familial hypertrophic cardiomyopathy.

    Cuda G, Perrotti N, Perticone F and Mattioli PL

    Dipartimento di Medicina Sperimentale e Clinica, Università di Reggio Calabria, Catanzaro, Italy.

    A previously undescribed de novo insertion-deletion mutation in the beta cardiac myosin heavy chain gene was found in a kindred with familial hypertrophic cardiomyopathy. In the mutated allele there is an inserted-deleted guanine at nucleotides 8823 and 8850 of the beta myosin heavy chain gene, resulting in a dramatic change of the amino acid sequence (AA 395-404). such a mutation, detected in the proband and in his son but not in the proband's parents, is likely to produce major impairment of myosin function.

    Heart (British Cardiac Society) 1996;76;5;451-2

  • Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg-->Cys mutation in the beta-myosin heavy chain gene: coexistence of sudden death and end-stage heart failure.

    Ko YL, Chen JJ, Tang TK, Cheng JJ, Lin SY, Liou YC, Kuan P, Wu CW, Lien WP and Liew CC

    Department of Internal Medicine, National Taiwan University Hospital, Taipei, Republic of China.

    Recent genotype-phenotype correlation studies in familial hypertrophic cardiomyopathy (FHC) have revealed that some mutations in the beta- myosin heavy chain (BMHC) gene may be associated with a high incidence of sudden death and a poor prognosis. Coexistence of sudden death and end-stage heart failure in several families with FHC has recently being reported; however, the genetic basis of such families has not been clearly demonstrated. A three-generation Chinese familial hypertrophic cardiomyopathy (FHC) family (family HLI) with two cases of end-stage heart failure and three cases of sudden death was analyzed. The average age of death in the affected members in this family was 34 years old. Genetic linkage analysis using polymorphisms in the (alpha- and beta-myosin heavy chain genes revealed that FHC in this family is significantly linked to the BMHC gene without recombinations. Single-strand conformation polymorphism analysis of exons 8, 9 and 13 to 23 in the BMHC gene showed a polymorphic band on exon 14 that is in complete linkage with the disease status in this family. DNA sequencing analysis in the affected members revealed an 453Arg-->Cys mutation in the BMHC gene. To our knowledge this is the first reported mutation of FHC in Chinese. Our data suggest that the 453Arg-->Cys mutation is associated with a malignant clinical course in FHC due not only to sudden death but also to end-stage heart failure.

    Human genetics 1996;97;5;585-90

  • A novel deletion mutation in the beta-myosin heavy chain gene found in Japanese patients with hypertrophic cardiomyopathy.

    Nakajima-Taniguchi C, Matsui H, Eguchi N, Nagata S, Kishimoto T and Yamauchi-Takihara K

    Department of Medicine III, Osaka University Medical School, Japan.

    Mutations in the cardiac beta-myosin heavy chain (MHC) gene of 50 Japanese patients with hypertrophic cardiomyopathy (HCM) were investigated by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. A novel deletion mutation was detected in exon 3 of the cardiac beta-MHC gene in a Japanese family with HCM. Sequencing analysis revealed a three nucleotide deletion at codon 10 leading to a deletion of a glycine residue, which has been conserved in the myosin gene from birds to humans. Because this deletion mutation was not detected in other healthy family members, it was suggested that this 10Gly deletion is the cause of HCM in this family. The same deletion mutation has been found in three other unrelated patients with HCM. This is the first report of a one codon deletion in the beta-MHC gene in patients with HCM.

    Journal of molecular and cellular cardiology 1995;27;12;2607-12

  • A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy.

    Nishi H, Kimura A, Harada H, Koga Y, Adachi K, Matsuyama K, Koyanagi T, Yasunaga S, Imaizumi T, Toshima H et al.

    Third Department of Internal Medicine, Kurume University School of Medicine, Japan.

    Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac beta-myosin-heavy-chain (beta-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac beta-MHC gene, ie, an alpha/beta hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood.

    We analyzed the structure of the cardiac beta-MHC gene from patients with HCM by using polymerase chain reaction-DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families.

    Conclusions: The Arg870His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac beta-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac beta-MHC gene.

    Circulation 1995;91;12;2911-5

  • [Genetic heterogeneity of hypertrophic cardiomyopathy in Japanese].

    Machida M

    Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.

    Familial hypertrophic cardiomyopathy (FHCM) is thought to be caused by missense mutations in cardiac beta-myosin heavy chain (beta-MHC) gene in 30-40% of affected Caucasian individuals. On the other hand, it has been reported that Japanese FHCM is closely linked to DNA marker PALB on chromosome 18q by linkage analysis. Therefore, in order to elucidate the etiological significance of missense mutations in beta-MHC gene in Japanese HCM patients, we have investigated the sequence variation in exon 3 to 25 of beta-MHC gene from 16 multiplex FHCM kindreds and 28 sporadic patients by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method. In this study we demonstrated one missense mutation (codon741: GlyGGG-->ArgAGG) in only one kindred among 16 multiplex Japanese kindreds with FHCM. Two synonymous mutations (codon715: TryTAC-->TryTAT, codon 989: IleATT-->IleATC) are demonstrated in another kindred. The same mutation in codon 989 is also detected in one sporadic patient. Furthermore, we performed linkage study with two DNA markers (F13B on chromosome 1q, D11S916: AMF185yal on chromosome 11p-q) which are recently reported to be linked with FHCM. Three and four families showed statistically negative linkage with F13B and D11S916 (AMF185yal), respectively. These results suggest that several responsible genes for HCM may exist in Japanese and principal responsible gene for Japanese HCM is different from it for Caucasian HCM.

    [Hokkaido igaku zasshi] The Hokkaido journal of medical science 1994;69;4;1024-34

  • A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy.

    Consevage MW, Salada GC, Baylen BG, Ladda RL and Rogan PK

    Department of Pediatrics, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17036.

    Human molecular genetics 1994;3;6;1025-6

  • Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy.

    Anan R, Greve G, Thierfelder L, Watkins H, McKenna WJ, Solomon S, Vecchio C, Shono H, Nakao S, Tanaka H et al.

    Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.

    Three novel beta cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change.

    Funded by: NHLBI NIH HHS: HL-42467, HL-46320, P50-HL-42267

    The Journal of clinical investigation 1994;93;1;280-5

  • Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

    Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Wisnewsky C, Bercovici J, Hengstenberg C, al-Mahdawi S et al.

    Institut National de la Sante et de la Recherche Médicale, U127, Hôpital Lariboisière, Paris, France.

    Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

    The Journal of clinical investigation 1993;92;6;2807-13

  • A missense mutation of cardiac beta-myosin heavy chain gene linked to familial hypertrophic cardiomyopathy in affected Japanese families.

    Harada H, Kimura A, Nishi H, Sasazuki T and Toshima H

    Third Department of Internal Medicine, Kurume University, School of Medicine, Japan.

    A novel missense mutation of the cardiac beta-myosin heavy chain gene was detected in five unrelated Japanese patients and their affected family members with hypertrophic cardiomyopathy (HCM) by using the polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis. Sequencing analysis revealed an A to G transition at codon 778 leading to replacement of the Asp residue, which is adjacent to the interaction sites of myosin heavy chain (MHC) with actin and is a conserved amino acid residue in various MHC across species, to the Gly residue. Linkage study of the mutation and two dinucleotides repeat markers of the cardiac beta-MHC gene in three affected families showed that the mutation was on the same haplotype of the cardiac beta-MHC gene and linked to HCM. These observations strongly suggest that the 778Asp to Gly mutation is the cause of HCM in these affected individuals.

    Biochemical and biophysical research communications 1993;194;2;791-8

Pubmed - other

  • The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population.

    Jääskeläinen P, Soranta M, Miettinen R, Saarinen L, Pihlajamäki J, Silvennoinen K, Tikanoja T, Laakso M and Kuusisto J

    Department of Medicine, University of Kuopio, Finland.

    Objectives: The aim of the study was to screen 36 unrelated patients with hypertrophic cardiomyopathy (HCM; 16 familial and 20 sporadic cases) from a genetically homogeneous area in eastern Finland for variants in the cardiac beta-myosin heavy chain (beta-MHC) and alpha-tropomyosin (alpha-TM) genes.

    Background: Mutations in the beta-MHC and alpha-TM genes have been reported to be responsible for 30% to 40% and less than 5% of familial HCM cases, respectively. However, most genetic studies have included patients from tertiary care centers and are subject to referral bias.

    Methods: Exons 3-26 and 40 of the beta-MHC gene and the nine exons of the alpha-TM gene were screened with the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method. Linkage analyses between familial HCM locus and two intragenic polymorphic markers (MYO I and MYO II) of the beta-MHC gene were performed in 16 familial HCM kindreds.

    Results: A previously reported Arg719Trp (arginine converted to tryptophan in codon 719) mutation of the beta-MHC gene was found in one proband and two relatives. In addition, a novel Asn696Ser (asparagine converted to serine in codon 696) substitution was found in one HCM patient. No linkage between familial HCM and the beta-MHC gene was observed in 16 familial kindreds. A previously reported Aspl75Asn (aspartic acid converted to asparagine in codon 175) mutation of the alpha-TM gene was found in four probands and 16 relatives. Mutations in the beta-MHC and alpha-TM genes accounted for 6% and 25% familial HCM cases and 3% and 11% of all cases, respectively.

    Conclusions: Our results indicate that the beta-MHC gene is not the predominant gene for HCM in the Finnish population, whereas HCM caused by the Aspl75Asn mutation of the a-TM gene is more common than previously reported.

    Journal of the American College of Cardiology 1998;32;6;1709-16

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