title: Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene.
abstract: Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Maria
authors.initials: M
authors.lastname: Savino
authors.forename: Domenico
authors.initials: D
authors.lastname: Bordo
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Bianca
authors.initials: B
authors.lastname: Rocca
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.forename: Filomena
authors.initials: F
authors.lastname: Di Bari
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Koivisto
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Raffaele
authors.initials: R
authors.lastname: Landolfi
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Zelante
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000473:pathology; D003638:Deafness / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D020409:Molecular Motor Proteins; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D009393:Nephritis / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains