MYH9 Spectrum of Autosomal-Dominant Giant Platelet Syndromes: Unexpected Association with Fibulin-1 Variant-D Inactivation

Amos Toren, Galit Rozenfeld-Granot, Karen E. Heath, Ninette Amariglio, Bianca Rocca, John Crosson, Charles J. Epstein, Ferdinando Laghi, Raffaele Landolfi, Lena E. Carlsson, Scott Argraves, Nicola Bizzaro, Marva Moxey-Mims, Frida Brok-Simoni, John A. Martignetti, Andreas Greinacher, Gideon Rechavi

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish
Pages (from-to)254-262
Number of pages9
JournalAmerican Journal of Hematology
Issue number4
StatePublished - Dec 2003
Externally publishedYes


FundersFunder number
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentP30HD028822


    • Antisense
    • Fibulin
    • Giant platelet syndrome
    • Myosin heavy chain 9


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