Abstract
Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of α-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated individuals and identified NBEAL2 as the causative gene; it has no previously known function but is a member of a gene family that is involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte formation.
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Acknowledgements
We thank S. Balasubramaniam, A. Coffey, the principal investigators of the CoLaus cohort14, R. Durbin, J. Durham, P. Ellis, K. Freson, GlaxoSmithKline collaborators, C. Langford and C. Scott for supporting different aspects of this study; see Supplementary Note for their specific contributions and for funding support.
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P.N. and W.H.O. conceived and designed the study. C.A.A. analyzed the sequencing data and performed statistical analysis. A.C. performed the zebrafish experiments. E.E.B., R.N.W.K. and J.S. performed the capillary sequencing. M.K. and P.B. analyzed the RNA sequencing and expression data. R.J.R. performed the protein structural modeling. P.A.S. generated the RNA sequencing and expression data. A.R. performed the microarray gene-expression analysis. G.J. and B.S. performed the evolutionary analyses. K.V. performed the megakaryocyte culture experiments. G.K. supervised the sample collection and exome sequencing. S.S. generated the whole-genome expression data for platelets. R.F., M.-C.A., A.N. and P.N. recruited and clinically characterized the cases. P.N. performed the electron microscopy experiments. C.A.A., A.C., P.N. and W.H.O. wrote the manuscript.
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Supplementary Methods, Supplementary Note, Supplementary Figures 1–15 and Supplementary Tables 1 and 2 (PDF 5037 kb)
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Albers, C., Cvejic, A., Favier, R. et al. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet 43, 735–737 (2011). https://doi.org/10.1038/ng.885
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DOI: https://doi.org/10.1038/ng.885
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