Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Toren, A. et al.

Toren, Rozenfeld-Granot, Heath, Amariglio, Rocca, Crosson, Epstein, Laghi, Landolfi, Carlsson, Argraves, Bizzaro, Moxey-Mims, Brok-Simoni, Martignetti, Greinacher, Rechavi,

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

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.[1]

References

MYH9 spectrum of autosomal-dominant giant platelet syndromes: unexpected association with fibulin-1 variant-D inactivation. Toren, A., Rozenfeld-Granot, G., Heath, K.E., Amariglio, N., Rocca, B., Crosson, J., Epstein, C.J., Laghi, F., Landolfi, R., Carlsson, L.E., Argraves, S., Bizzaro, N., Moxey-Mims, M., Brok-Simoni, F., Martignetti, J.A., Greinacher, A., Rechavi, G. Am. J. Hematol. (2003) [Pubmed]

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