G2Cdb::Human Disease report

Disease id
D00000134
Name
MYH9-related disease
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (16818291) Microinsertion (MI) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (16806139) Single nucleotide polymorphism (SNP) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (16162639) Nonsense (No) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (16098078) Microinsertion (MI) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (16077952) Polymorphism (P) N
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (15667538) Frameshift mutation (FS) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (15613099) Deletion (D) Y
G00002004 MYH9
myosin, heavy chain 9, non-muscle
Y (15339844) Polymorphism (P) Y

References

  • Analysis of clinical manifestations, mutant gene and encoded protein in two Chinese MYH9-related disease families.

    Yi Y, Sen Zhang G, Xu M, San Ling Z, Ru Shao X, Zeng Li J and Ma J

    Division of Hematology/Institute of Molecular Hematology, the Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.

    Background: MYH9-related disease is a rare autosomal dominant disorder characterized by the triad of giant platelet, thrombocytopenia and inclusion bodies in neutrophil. In recent years, much progress has been made in the investigation of its clinical feature and pathogenesis.

    Methods: Clinical manifestations were analyzed in two Chinese MYH9-related disease families. Polymerase chain reaction (PCR), DNA sequencing and CpoI restrictive endonuclease map analysis were used to identify spot mutation in nonmuscle myosin heavy chain 9 (MYH9) gene. Indirect immunofluence combined propidium iodine (PI) nuclei count-staining technology was applied to probe nonmuscle myosin heavy chain IIA (NMMHC-A) in MYH9-related disease neutrophils and platelets. Western blot was undergone to examine the expression of NMMHC-A in MYH9-related disease patients.

    Results: All of the patients manifested with the typical triad, mild to moderate bleeding tendency were their common clinical feature, some patients were accompanied by renal lesion. G5521A mutation in MYH9 gene was identified in both families. Spindle-like inclusions with yellow fluorescence in MYH9-related disease neutrophils were clearly revealed by indirect immunofluence combined PI nuclei count-staining technology, which matched very well with the inclusions, detected by Wright-Giemsa's stain. An upregulation of NMMHC-A in MYH9-related disease neutrophils was observed by Western blotting analysis.

    Conclusion: Mutation of MYH9 gene exists in cases of Chinese MYH9-related disease. In the two families, the point mutation was located in exon 38(G5521A), and the transference rule of the MYH9 gene mutation is corresponding with clinical phenotype distribution. Indirect immunofluorescence combining with PI nuclei staining technology is sensitive and more specific than Wright-Giemsa's staining in detecting MYH9-related disease inclusions, with which we might easily distinguish MYH9-related disease inclusions from infection-associated inclusions. The expression of the NMMHC-A in MYH9-related disease neutrophils was upregulated than normal control.

    Clinica chimica acta; international journal of clinical chemistry 2006;373;1-2;49-54

  • Hematologic and genetic characterization of an MYH9-related disorder in a Chinese family.

    Ma ES, Wong CL, Shek TW and Hui SP

    We describe a Chinese family with an MYH9-related disorder in which a novel mutation V1516L at exon 31 of the MYH9 gene was identified. To the best of our knowledge, this is the first reported Chinese family with MYH9 mutation and supports the pan-ethnic nature of the disorder.

    Haematologica 2006;91;7;1002-3

  • Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.

    Pecci A, Canobbio I, Balduini A, Stefanini L, Cisterna B, Marseglia C, Noris P, Savoia A, Balduini CL and Torti M

    Department of Internal Medicine, University of Pavia, Italy. alessandro.pecci@unipv.it

    Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinical phenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associated with deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects are either completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiency or a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated 11 patients from six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in platelets and granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulating progenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that all the investigated patients had a 50% reduction of NMMHC-IIA expression in platelets and that a similar defect was present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of platelets and Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulocytes, the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and Mks, and we found that wild-type protein was sequestered within most of the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies. The finding that the same mutations act through different mechanisms in different cells is surprising and requires further investigation.

    Funded by: Telethon: GP0019Y01, TGM06S01

    Human molecular genetics 2005;14;21;3169-78

  • Dissecting clinical findings: platelet defects segregate independently of deafness and cataract in a family affected by an apparent syndromic form of macrothrombocytopenia.

    Gangarossa S, Seri M, Pecci A, Di Bari F, Cusano R, Balduini C, Gasparini P and Savoia A

    ASL 7 Ragusa, Università di Bologna, Italy.

    We studied a family with a suspected diagnosis of MYH9-related disease, which is one of the most common forms of autosomal dominant macrothrombocytopenias associated with hearing impairment, cataracts and nephritis. No mutation of the MYH9 gene was identified. Moreover, the A156V variant of the GPIbalpha gene, responsible for 30% of macrothrombocytopenias in Italy, was not detected in the family. Therefore, we hypothesized that the clinical symptoms were caused by mutations in different genes. The screening of the candidate genes for deafness and/or cataract allowed us to identify two variants, M34T and S19T, of the GJB2 gene in family members with hearing impairment. Because of the relatively common occurrence of inherited hearing loss and, at least in the Mediterranean area, of platelet macrocytosis, the two traits occurred by chance in the same family and mimicked the MYH9-related disease.

    Funded by: Telethon: F04001

    International journal of molecular medicine 2005;16;3;437-41

  • Genotype-phenotype correlation in MYH9-related thrombocytopenia.

    Dong F, Li S, Pujol-Moix N, Luban NL, Shin SW, Seo JH, Ruiz-Saez A, Demeter J, Langdon S and Kelley MJ

    Department of Medicine, Duke University Medical Center and Hematology/Oncology, Durham Veterans Affairs Hospital, Durham, NC 27705, USA.

    Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.

    Funded by: NCI NIH HHS: 1U01-CA-96123-01, 5R21 CA91565-02; NHLBI NIH HHS: 1R01HL66192-02

    British journal of haematology 2005;130;4;620-7

  • First description of somatic mosaicism in MYH9 disorders.

    Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M and Saito H

    Department of Haemostasis and Thrombosis, Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan. kunishis@nnh.hosp.go.jp

    MYH9 disorders are characterized by giant platelets, thrombocytopenia, and Dohle body-like cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, which encodes non-muscle myosin heavy chain-A (NMMHCA). These disorders are known to be transmitted in an autosomal dominant manner, although about 20% of cases are considered to be sporadic. We report here the first case of a MYH9 disorder because of somatic mosaicism. The patient was the father of a male with typical May-Hegglin anomaly. The father had normal platelet counts, however, both normal-sized and giant platelets were observed on his peripheral blood smears. In addition, 14% of neutrophils contained inclusion bodies and the rest showed a normal morphology. Quantitative fluorescent polymerase chain reaction analysis showed that only 6% of DNA from peripheral blood leucocytes harboured the mutation. The mosaicism was demonstrated at a similar rate in different tissues, buccal mucosa cells and hair bulb cells, implying that the mutation had occurred before gastrulation. Mosaicism might account for some de novo mutations in MYH9 disorders.

    British journal of haematology 2005;128;3;360-5

  • Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.

    Franke JD, Dong F, Rickoll WL, Kelley MJ and Kiehart DP

    Department of Biology, Developmental Cell and Molecular Biology Group, Duke University Medical Center, Durham, NC 27708-1000, USA.

    MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the alpha-helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease.

    Funded by: NHLBI NIH HHS: HL 66192; NIGMS NIH HHS: GM 33830

    Blood 2005;105;1;161-9

  • Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness.

    Kunishima S, Matsushita T, Shiratsuchi M, Ikuta T, Nishimura J, Hamaguchi M, Naoe T and Saito H

    Department of Hemostasis and Thrombosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan. kunishis@nnh.hosp.go.jp

    MYH9 disorders are autosomal-dominant macrothrombocytopenias with leukocyte inclusions caused by mutations in the MYH9 gene, which encodes the non-muscle myosin heavy chain-A (NMMHCA). We report a patient with an MYH9 disorder who presented with macrothrombocytopenia without leukocyte inclusions and severe bilateral sensory deafness. Conventional May-Grunwald-Giemsa staining failed to detect granulocyte cytoplasmic inclusions, whereas immunofluorescence analysis clearly demonstrated abnormal neutrophil NMMHCA localization. Genetic analyses revealed a novel heterozygous 18 base deletion in MYH9, leading to a six-amino acid in-frame deletion (N76_S81del) in NMMHCA. These results further support the usefulness of immunofluorescence analysis in differential diagnosis of MYH9 disorders.

    European journal of haematology 2005;74;1;1-5

Literature (8)

Pubmed - human_disease

  • Hematologic and genetic characterization of an MYH9-related disorder in a Chinese family.

    Ma ES, Wong CL, Shek TW and Hui SP

    We describe a Chinese family with an MYH9-related disorder in which a novel mutation V1516L at exon 31 of the MYH9 gene was identified. To the best of our knowledge, this is the first reported Chinese family with MYH9 mutation and supports the pan-ethnic nature of the disorder.

    Haematologica 2006;91;7;1002-3

  • Dissecting clinical findings: platelet defects segregate independently of deafness and cataract in a family affected by an apparent syndromic form of macrothrombocytopenia.

    Gangarossa S, Seri M, Pecci A, Di Bari F, Cusano R, Balduini C, Gasparini P and Savoia A

    ASL 7 Ragusa, Università di Bologna, Italy.

    We studied a family with a suspected diagnosis of MYH9-related disease, which is one of the most common forms of autosomal dominant macrothrombocytopenias associated with hearing impairment, cataracts and nephritis. No mutation of the MYH9 gene was identified. Moreover, the A156V variant of the GPIbalpha gene, responsible for 30% of macrothrombocytopenias in Italy, was not detected in the family. Therefore, we hypothesized that the clinical symptoms were caused by mutations in different genes. The screening of the candidate genes for deafness and/or cataract allowed us to identify two variants, M34T and S19T, of the GJB2 gene in family members with hearing impairment. Because of the relatively common occurrence of inherited hearing loss and, at least in the Mediterranean area, of platelet macrocytosis, the two traits occurred by chance in the same family and mimicked the MYH9-related disease.

    Funded by: Telethon: F04001

    International journal of molecular medicine 2005;16;3;437-41

  • Genotype-phenotype correlation in MYH9-related thrombocytopenia.

    Dong F, Li S, Pujol-Moix N, Luban NL, Shin SW, Seo JH, Ruiz-Saez A, Demeter J, Langdon S and Kelley MJ

    Department of Medicine, Duke University Medical Center and Hematology/Oncology, Durham Veterans Affairs Hospital, Durham, NC 27705, USA.

    Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.

    Funded by: NCI NIH HHS: 1U01-CA-96123-01, 5R21 CA91565-02; NHLBI NIH HHS: 1R01HL66192-02

    British journal of haematology 2005;130;4;620-7

  • First description of somatic mosaicism in MYH9 disorders.

    Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M and Saito H

    Department of Haemostasis and Thrombosis, Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan. kunishis@nnh.hosp.go.jp

    MYH9 disorders are characterized by giant platelets, thrombocytopenia, and Dohle body-like cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, which encodes non-muscle myosin heavy chain-A (NMMHCA). These disorders are known to be transmitted in an autosomal dominant manner, although about 20% of cases are considered to be sporadic. We report here the first case of a MYH9 disorder because of somatic mosaicism. The patient was the father of a male with typical May-Hegglin anomaly. The father had normal platelet counts, however, both normal-sized and giant platelets were observed on his peripheral blood smears. In addition, 14% of neutrophils contained inclusion bodies and the rest showed a normal morphology. Quantitative fluorescent polymerase chain reaction analysis showed that only 6% of DNA from peripheral blood leucocytes harboured the mutation. The mosaicism was demonstrated at a similar rate in different tissues, buccal mucosa cells and hair bulb cells, implying that the mutation had occurred before gastrulation. Mosaicism might account for some de novo mutations in MYH9 disorders.

    British journal of haematology 2005;128;3;360-5

  • Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.

    Franke JD, Dong F, Rickoll WL, Kelley MJ and Kiehart DP

    Department of Biology, Developmental Cell and Molecular Biology Group, Duke University Medical Center, Durham, NC 27708-1000, USA.

    MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the alpha-helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease.

    Funded by: NHLBI NIH HHS: HL 66192; NIGMS NIH HHS: GM 33830

    Blood 2005;105;1;161-9

  • Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness.

    Kunishima S, Matsushita T, Shiratsuchi M, Ikuta T, Nishimura J, Hamaguchi M, Naoe T and Saito H

    Department of Hemostasis and Thrombosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan. kunishis@nnh.hosp.go.jp

    MYH9 disorders are autosomal-dominant macrothrombocytopenias with leukocyte inclusions caused by mutations in the MYH9 gene, which encodes the non-muscle myosin heavy chain-A (NMMHCA). We report a patient with an MYH9 disorder who presented with macrothrombocytopenia without leukocyte inclusions and severe bilateral sensory deafness. Conventional May-Grunwald-Giemsa staining failed to detect granulocyte cytoplasmic inclusions, whereas immunofluorescence analysis clearly demonstrated abnormal neutrophil NMMHCA localization. Genetic analyses revealed a novel heterozygous 18 base deletion in MYH9, leading to a six-amino acid in-frame deletion (N76_S81del) in NMMHCA. These results further support the usefulness of immunofluorescence analysis in differential diagnosis of MYH9 disorders.

    European journal of haematology 2005;74;1;1-5

Pubmed - other

  • Analysis of clinical manifestations, mutant gene and encoded protein in two Chinese MYH9-related disease families.

    Yi Y, Sen Zhang G, Xu M, San Ling Z, Ru Shao X, Zeng Li J and Ma J

    Division of Hematology/Institute of Molecular Hematology, the Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.

    Background: MYH9-related disease is a rare autosomal dominant disorder characterized by the triad of giant platelet, thrombocytopenia and inclusion bodies in neutrophil. In recent years, much progress has been made in the investigation of its clinical feature and pathogenesis.

    Methods: Clinical manifestations were analyzed in two Chinese MYH9-related disease families. Polymerase chain reaction (PCR), DNA sequencing and CpoI restrictive endonuclease map analysis were used to identify spot mutation in nonmuscle myosin heavy chain 9 (MYH9) gene. Indirect immunofluence combined propidium iodine (PI) nuclei count-staining technology was applied to probe nonmuscle myosin heavy chain IIA (NMMHC-A) in MYH9-related disease neutrophils and platelets. Western blot was undergone to examine the expression of NMMHC-A in MYH9-related disease patients.

    Results: All of the patients manifested with the typical triad, mild to moderate bleeding tendency were their common clinical feature, some patients were accompanied by renal lesion. G5521A mutation in MYH9 gene was identified in both families. Spindle-like inclusions with yellow fluorescence in MYH9-related disease neutrophils were clearly revealed by indirect immunofluence combined PI nuclei count-staining technology, which matched very well with the inclusions, detected by Wright-Giemsa's stain. An upregulation of NMMHC-A in MYH9-related disease neutrophils was observed by Western blotting analysis.

    Conclusion: Mutation of MYH9 gene exists in cases of Chinese MYH9-related disease. In the two families, the point mutation was located in exon 38(G5521A), and the transference rule of the MYH9 gene mutation is corresponding with clinical phenotype distribution. Indirect immunofluorescence combining with PI nuclei staining technology is sensitive and more specific than Wright-Giemsa's staining in detecting MYH9-related disease inclusions, with which we might easily distinguish MYH9-related disease inclusions from infection-associated inclusions. The expression of the NMMHC-A in MYH9-related disease neutrophils was upregulated than normal control.

    Clinica chimica acta; international journal of clinical chemistry 2006;373;1-2;49-54

  • Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.

    Pecci A, Canobbio I, Balduini A, Stefanini L, Cisterna B, Marseglia C, Noris P, Savoia A, Balduini CL and Torti M

    Department of Internal Medicine, University of Pavia, Italy. alessandro.pecci@unipv.it

    Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinical phenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associated with deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects are either completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiency or a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated 11 patients from six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in platelets and granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulating progenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that all the investigated patients had a 50% reduction of NMMHC-IIA expression in platelets and that a similar defect was present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of platelets and Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulocytes, the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and Mks, and we found that wild-type protein was sequestered within most of the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies. The finding that the same mutations act through different mechanisms in different cells is surprising and requires further investigation.

    Funded by: Telethon: GP0019Y01, TGM06S01

    Human molecular genetics 2005;14;21;3169-78

© 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).

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