Robert Flaumenhaft, MD, PhD
Dr. Flaumenhaft indicated no relevant conflicts of interest.
Gunay-Aygun M, Falik-Zaccai TC, Vilboux T, et al. NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules. Nat Genet. 2011;43:732-734.
Albers CA, Cvejic A, Favier R, et al. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet. 2011;43:735-737.
Kahr WH, Hinckley J, Li L, et al. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nat Genet. 2011;43:738-740.
In 1971, Dr. Giovanni Raccuglia published a curious case of an 11-year-old boy with a bleeding tendency out of proportion to his thrombocytopenia.1 His platelets appeared large, gray, and agranular upon Wright staining. The plot thickened over the next 40 years, as several dozen patients were found to be affected by the syndrome. The tell-tale signs of the disorder were large platelets with a distinct deficiency of α-granules. In contrast to other known platelet granule abnormalities, such as Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome, the dense granules in victims of gray platelet syndrome remained unaffected. These findings led investigators to ask what gene was responsible for this syndrome and how the defect impaired α-granule formation without affecting the formation of dense granules. The mystery spawned a multi-national search for the defective gene. Approximately one year ago, the search intensified as a team of Israeli and American investigators narrowed the location of the causative gene to a small piece of chromosome 3p, a region that contained 165 gene suspects.2 A second team confirmed this location and narrowed the lineup of suspects.3 The precise identity of the culprit gene, however, remained unknown. Now, after decades of searching, the gene responsible for gray platelet syndrome (the BEACH domain-encoding gene, NBEAL2) has been finally apprehended.
In an unusual twist to a genetic caper, the identity of NBEAL2 as the causative gene in gray platelet syndrome was identified by three investigative teams using three different experimental strategies and published simultaneously. The U.S.-Israeli group performed genome-wide linkage analysis and homozygosity mapping of 25 individuals with gray platelet syndrome. Sequencing of exons in 15 unrelated affected individuals demonstrated mutations in NBEAL2. In a British-French collaboration, whole-exome sequencing of four unrelated patients was performed. Previously observed variants and those not likely to affect platelet function were filtered. All four subjects demonstrated two mutations in NBEAL2. A third team, including investigators from the United States and Canada, used next-generation RNA sequence analysis of platelets from an individual with gray platelet syndrome to identify atypical transcripts derived from genes located in a 2.7 MB region previously identified by this group to be linked to gray platelet syndrome. This analysis demonstrated intron retention in transcripts of NBEAL2 in affected subjects. Sequencing of genomic NBEAL2 in the affected individual and two other families with gray platelet syndrome confirmed that NBEAL2 was the affected gene. Together, these studies provide irrefutable evidence of the role of NBEAL2 in gray platelet syndrome.
Gray platelet syndrome is a rare, autosomal, recessive disorder characterized by the absence of α-granules. The identification of NBEAL2 as the affected gene in this syndrome will provide a means to definitively diagnose this disorder. Determination of the causative gene of gray platelet syndrome also provides a new direction in the study of α-granule biogenesis. NBEAL2 encodes neurobeachin-like protein 2, a member of a family of proteins containing a BEACH domain. These domains were originally identified in LYST, the protein that is mutated in Chédiak- Higashi syndrome, in which dense granules are deficient. These proteins are known to function in vesicle trafficking and membrane dynamics. Further studies will be required to determine the role of neurobeachin-like protein 2 in packing and sorting platelet α-granules.
- Raccuglia G. Gray platelet syndrome. A variety of qualitative platelet disorder. Am J Med. 1971;51:818-828.
- Gunay-Aygun M, Zivony-Elboum Y, Gumruk F, et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood. 2010;116:4990-5001.
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