NBEAL2 is mutated in Gray Platelet Syndrome and required for biogenesis of platelet alpha-granules

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NHGRI	GEN/GENOM-21

* FARE Award Winner

Authors

• T Vilboux
• T Falik-Zaccai
• Y Zivony-Elboum
• F Gumruk
• M Cetin
• CF Boerkoel
• Y Huang
• D Maynard
• H Dorward
• K Berger
• R Kleta
• Y Anikster
• BE Kehrel
• K Jurk
• P Cruz
• JC Mullikin
• JG White
• M Huizing
• WA Gahl
• M Gunay-Aygun

Abstract

Gray Platelet Syndrome (GPS) is a rare autosomal recessive disorder characterized by bleeding tendency, thrombocytopenia, myelofibrosis and large platelets that lack α-granules. The causative gene has been sought for decades. We mapped the locus for GPS to a 9.4Mb interval on 3p21.1-22.1 that includes 197 protein-coding genes. We sequenced these genes using a combination of next generation and Sanger sequencing in 15 independent GPS families. We identified 15 different mutations in NBEAL2 (neurobeachin-like 2). The protein encoded has no known function, but contains three domains (BEACH, ARM and WD40) that are also found in LYST, a lysosomal trafficking regulator protein defective in Chédiak-Higashi syndrome. RNA analysis showed that at least seven NBEAL2 mRNA transcripts are expressed in hematopoietic cells, including megakaryocytes and platelets. Mass spectrometry of discontinuous sucrose gradient platelet fractions identified NBEAL2 localization to the platelet dense tubular system (endoplasmic reticulum). Microarray data in GPS fibroblasts showed overexpression of fibronectin, essential for proplatelet formation in cultured megakaryocytes and critical for megakaryocyte-matrix interactions. This could explain the myelofibrosis seen in GPS patients and therefore can be explored as a therapeutic target. Understanding NBEAL2 function will likely lead to the discovery of novel pathways of organelle formation and maturation.

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