title: MYH9 spectrum of autosomal-dominant giant platelet syndromes: unexpected association with fibulin-1 variant-D inactivation.
abstract: The autosomal-dominant giant platelet syndromes (Fechtner, Epstein, and Sebastian platelet syndromes and May-Hegglin anomaly) represent a group of disorders characterized by variable degrees of macrothrombocytopenia with further combinations of neutrophil inclusion bodies and Alport-like syndrome manifestations, namely, deafness, renal disease, and eye abnormalities. The disease-causing gene of these giant platelet syndromes was previously mapped by us to chromosome 22. Following their successful mapping, these syndromes were shown to represent a broad phenotypic spectrum of disorders caused by different mutations in the nonmuscle myosin heavy chain 9 gene (MYH9). In this study, we examined the potential role of another gene, fibulin-1, encoding an extracellular matrix protein as a disease modifier. Eight unrelated families with autosomal-dominant giant platelet syndromes were studied for DNA sequence mutations and expression of the four fibulin-1 splice variants (A-D). A mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family, whereas no MYH9 mutations were identified. Unexpectedly, fibulin-1 variant D expression was absent in affected individuals from all eight families and coupled with expression of a putative antisense RNA. Transfection of the putative antisense RNA into H1299 cells abolished variant D expression. Based on the observation that only affected individuals lack variant D expression and demonstrate antisense RNA overexpression, we suggest that these autosomal-dominant giant platelet syndromes are associated, and may be modified, by aberrant antisense gene regulation of the fibulin-1 gene.
authors.affiliation: Pediatric Hemato-Oncology Department and the Institute of Hematology, the Chaim Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Israel. amost@post.tau.ac.il
authors.forename: Amos
authors.initials: A
authors.lastname: Toren
authors.forename: Galit
authors.initials: G
authors.lastname: Rozenfeld-Granot
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Bianca
authors.initials: B
authors.lastname: Rocca
authors.forename: John
authors.initials: J
authors.lastname: Crosson
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Laghi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Landolfi
authors.forename: Lena E
authors.initials: LE
authors.lastname: Carlsson
authors.forename: Scott
authors.initials: S
authors.lastname: Argraves
authors.forename: Nicola
authors.initials: N
authors.lastname: Bizzaro
authors.forename: Marva
authors.initials: M
authors.lastname: Moxey-Mims
authors.forename: Frida
authors.initials: F
authors.lastname: Brok-Simoni
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
mesh_terms: D001483:Base Sequence; D001606:Bernard-Soulier Syndrome / Q000209:etiology / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D020868:Gene Silencing; D005799:Genes, Dominant; D006801:Humans; D020409:Molecular Motor Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference; D022821:RNA Splice Sites / Q000235:genetics; D016372:RNA, Antisense / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D016372:RNA, Antisense; C060820:fibulin; D018995:Myosin Heavy Chains