title: Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.
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 Döhle-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.
authors.affiliation: University of Geneva, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rideau
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Bochaton-Piallat
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.forename: Antoine
authors.initials: A
authors.lastname: Geinoz
authors.forename: Giulio
authors.initials: G
authors.lastname: Gabbiani
authors.forename: Torsten
authors.initials: T
authors.lastname: Schwede
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Photis
authors.initials: P
authors.lastname: Beris
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000473:pathology; D001792:Blood Platelets / Q000473:pathology*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003599:Cytoskeleton / Q000648:ultrastructure*; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D020409:Molecular Motor Proteins; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D011489:Protein Denaturation; D012333:RNA, Messenger / Q000378:metabolism; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D012333:RNA, Messenger; D018995:Myosin Heavy Chains