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NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules

Nature Genetics volume 43, pages 732–734 (2011)Cite this article

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Abstract

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder that is characterized by large platelets that lack α-granules. Here we show that mutations in NBEAL2 (neurobeachin-like 2), which encodes a BEACH/ARM/WD40 domain protein, cause GPS and that megakaryocytes and platelets from individuals with GPS express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.

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Figure 1: Cellular studies of GPS.

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Acknowledgements

We thank all of our subjects with GPS and their families for their cooperation; the NIH Intramural Sequencing Center for performing the whole-exome sequencing and analysis; A. Nurden for the French patient; I. Bernardini and R. Fisher for technical assistance; H. Edwards, L. Riley, K. Patzel, P. Tanpaiboon, J. Chezar and J. Manaster for DNA sequencing assistance; T. Markello for the SNP array; and I. Maric, S. Gucer and I. Kuzu for assistance with bone marrow slides. This study was supported by the Intramural Research Programs of the National Human Genome Research Institute and the NIH Clinical Center and by the Israeli Ministry of Justice; Izvonot Fund, grants 84/2004, 85/2004 and 9090-25/2007 to T.C.F.-Z.

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Author notes

  1. Meral Gunay-Aygun and Tzipora C Falik-Zaccai: These authors contributed equally to this work.

Authors and Affiliations

  1. Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Meral Gunay-Aygun, Thierry Vilboux, Cornelius F Boerkoel, Yan Huang, Dawn Maynard, Heidi Dorward, Katherine Berger, Robert Kleta, Marjan Huizing & William A Gahl

  2. Office of Rare Diseases Research, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA

    Meral Gunay-Aygun & William A Gahl

  3. Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel

    Tzipora C Falik-Zaccai, Yifat Zivony-Elboum, Morad Khayat & Nehama Kfir

  4. Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

    Tzipora C Falik-Zaccai

  5. Pediatric Hematology Unit, Hacettepe University Children's Hospital, Ankara, Turkey

    Fatma Gumruk & Mualla Cetin

  6. Metabolic Disease Unit, Edmond and Lily Safra Children′s Hospital, Sheba Medical Center, Tel Aviv, Israel

    Yair Anikster

  7. Sackler Medical School, Tel Aviv, Israel

    Yair Anikster

  8. Department of Hematology, Ankara University Faculty of Medicine, Ankara, Turkey

    Mutlu Arat

  9. Division of Pediatric Hematology/Oncology, Penn State Hershey Children's Hospital, Hershey, Pennsylvania

    Andrew S Freiberg

  10. Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University Hospital Münster, Münster, Germany

    Beate E Kehrel & Kerstin Jurk

  11. US National Institutes of Health (NIH) Intramural Sequencing Center, NIH, Bethesda, Maryland, USA.,

    Pedro Cruz & Jim C Mullikin

  12. Department of Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota, USA

    James G White

Authors
  1. Meral Gunay-Aygun
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  2. Tzipora C Falik-Zaccai
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  6. Mualla Cetin
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  7. Morad Khayat
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  8. Cornelius F Boerkoel
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  10. Yan Huang
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  16. Mutlu Arat
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  20. Pedro Cruz
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  21. Jim C Mullikin
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  22. James G White
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  24. William A Gahl
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Contributions

M.G.-A. is the principal investigator of clinical trials NCT00069680 (Genetic Analysis of Gray Platelet Syndrome) and NCT00086476 (Investigations of Megakaryocytes from Patients with Abnormal Platelet Vesicles); M.G.-A. wrote the manuscript and cultured megakaryocytes; M.G.-A., W.A.G. and T.C.F.-Z. designed and supervised research; M.G.-A., T.C.F.-Z. and T.V. analyzed clinical and molecular data; T.C.F.-Z., is the principal investigator of the Israeli protocol 'Clinical and Genetic Analysis of Gray Platelet Syndrome'; W.A.G. is the principal investigator of clinical trial NCT00369421 (Diagnosis and Treatment of Patients With Inborn Errors of Metabolism) and accountable investigator of clinical trial NCT00069680 (Genetic Analysis of Gray Platelet Syndrome); M.G.-A., T.V., T.C.F.-Z., J.C.M., C.F.B. and M.H. supervised DNA sequencing; M.G.-A., T.V., Y.Z.-E., F.G., M.C., M.K., C.F.B., N.K., Y.H., K.B., R.K. and P.C., performed DNA sequencing; M.G.-A., T.C.F.-Z., F.G., M.C., M.K., N.K., R.K., Y.A., M.A., A.S.F., B.E.K., K.J. and J.G.W. recruited patients and provided clinical data; J.G.W. performed electron microscopy; D.M. performed proteomic analysis; H.D. cultured fibroblasts; T.C.F.-Z., T.V., Y.Z.-E., F.G., M.C., M.K., C.F.B., N.K., Y.H., D.M., H.D., K.B., R.K., Y.A., M.A., A.S.F., B.E.K., K.J., P.C., J.C.M., J.G.W., M.H. and W.A.G. participated in preparing the manuscript.

Corresponding author

Correspondence to Meral Gunay-Aygun.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Supplementary Table 1 and Supplementary Methods (PDF 2002 kb)

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Gunay-Aygun, M., Falik-Zaccai, T., Vilboux, T. et al. NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules. Nat Genet 43, 732–734 (2011). https://doi.org/10.1038/ng.883

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