MYH9 spectrum of autosomal-dominant giant platelet syndromes: unexpected association with fibulin-1 variant-D inactivation

A Toren, G Rozenfeld Granot, Ke Heath, N Amariglio, Bianca Rocca, J Crosson, Cj Epstein, F Laghi, Raffaele Landolfi, Le Carlsson, S Argraves, N Bizzaro, M Moxey Mims, F Brok Simoni, Ja Martignetti, A Greinacher, G. Rechavi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

20 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)254-262
Numero di pagine9
RivistaAmerican Journal of Hematology
Stato di pubblicazionePubblicato - 2003


  • Base Sequence
  • Bernard-Soulier Syndrome
  • Calcium-Binding Proteins
  • DNA Mutational Analysis
  • Family Health
  • Gene Silencing
  • Genes, Dominant
  • Humans
  • Molecular Motor Proteins
  • Molecular Sequence Data
  • Mutation
  • Myosin Heavy Chains
  • Protein Isoforms
  • RNA Interference
  • RNA Splice Sites
  • RNA, Antisense


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