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Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome

Deutsch, Samuel
Bochaton-Piallat, Marie-Luce
Schwede, Torsten
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Published in Blood. 2003, vol. 102, no. 2, p. 529-534
Abstract May-Hegglin anomaly (MHA), Fechtner syndrome (FTNS), Sebastian syndrome (SBS), and Epstein syndrome (EPS) are a group of rare, autosomal dominant disorders characterized by thrombocytopenia, giant platelets, and Dohle-like inclusion bodies, together with variable manifestations of Alport-like symptoms that include high-tone sensorineural deafness, cataracts, and nephritis. These disorders result from mutations in the MYH9 gene, which encodes for the nonmuscle myosin heavy chain A protein (also known as NMMHC-A). To date 20 different mutations have been characterized for this gene, but no clear phenotype-genotype correlation has been established, and very little is known regarding the molecular pathogenesis of this group of diseases. Here, we describe 2 new families with MHA/FTNS phenotypes that have been characterized in terms of their mutations, protein localization in megakaryocytes, protein expression, and mRNA stability. Our findings suggest that, at least for the Asp1424Asn mutation in the MYH9 gene, the phenotypes result from a highly unstable protein. No abnormalities in protein localization or mRNA stability were observed. We hypothesize that haploinsufficiency of the MYH9 results in a failure to properly reorganize the cytoskeleton in megakaryocytes as required for efficient platelet production.
Keywords AdultAllelesAmino Acid SubstitutionBlood Platelet Disorders/ genetics/pathologyBlood Platelets/ pathologyChromosomes, Human, Pair 22/ geneticsCytoskeleton/ ultrastructureDNA Mutational AnalysisFemaleGenes, DominantHearing Loss, Sensorineural/geneticsHumansInclusion Bodies/ultrastructureMaleMegakaryocytes/ pathologyMolecular Motor ProteinsMutation, MissenseMyosin Heavy Chains/chemistry/ genetics/physiologyPedigreePhenotypeProtein DenaturationRNA, Messenger/metabolismSyndromeThrombocytopenia/genetics/pathology
PMID: 12649151
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Research group Analyses cellulaires et moléculaires des hémopathies malignes (929)
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DEUTSCH, Samuel et al. Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. In: Blood, 2003, vol. 102, n° 2, p. 529-534. doi: 10.1182/blood-2002-09-2783 https://archive-ouverte.unige.ch/unige:8725

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Deposited on : 2010-07-12

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