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Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome

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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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Figure 1: Mutations in NBEAL2 in individuals with GPS.

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ArrayExpress

NCBI Reference Sequence

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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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Author notes

  1. Cornelis A Albers, Ana Cvejic, Paquita Nurden and Willem H Ouwehand: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Cornelis A Albers, Ana Cvejic, Ross N W Kettleborough & Willem H Ouwehand

  2. Department of Haematology, University of Cambridge & NHS Blood and Transplant, Cambridge, UK

    Cornelis A Albers, Ana Cvejic, Evelien E Bouwmans, Graham Kiddle, Peter A Smethurst, Jonathan Stephens, Katrin Voss, Augusto Rendon & Willem H Ouwehand

  3. Département d'Hématologie, Assistance-Publique Hôpitaux de Paris, Centre de Référence des Pathologies Plaquettaires, Hôpital Armand Trousseau, Paris, France

    Rémi Favier

  4. Institut National de la Santé et de la Recherche Médicale U1009, Villejuif, France

    Rémi Favier

  5. Institut National de la Santé et de la Recherche Médicale U626, Faculté de Médecine, Marseille, France

    Marie-Christine Alessi

  6. European Molecular Biology Laboratory—European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Paul Bertone, Gregory Jordan, Myrto Kostadima & Botond Sipos

  7. Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    Randy J Read

  8. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

    Suthesh Sivapalaratnam

  9. Laboratoire d'Hématologie, Centre de Référence des Pathologies Plaquettaires, Hopital Xavier Arnozan, Pessac, France

    Alan Nurden & Paquita Nurden

  10. Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, UK

    Augusto Rendon

Authors
  1. Cornelis A Albers
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  2. Ana Cvejic
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  3. Rémi Favier
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  4. Evelien E Bouwmans
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  5. Marie-Christine Alessi
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  6. Paul Bertone
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  7. Gregory Jordan
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  8. Ross N W Kettleborough
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  9. Graham Kiddle
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  10. Myrto Kostadima
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  11. Randy J Read
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  12. Botond Sipos
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  13. Suthesh Sivapalaratnam
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  14. Peter A Smethurst
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  15. Jonathan Stephens
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  16. Katrin Voss
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  17. Alan Nurden
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  18. Augusto Rendon
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  19. Paquita Nurden
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  20. Willem H Ouwehand
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Contributions

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.

Corresponding authors

Correspondence to Cornelis A Albers or Willem H Ouwehand.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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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