Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome

Abstract

Next-generation RNA sequence analysis of platelets from an individual with autosomal recessive gray platelet syndrome (GPS, MIM139090) detected abnormal transcript reads, including intron retention, mapping to NBEAL2 (encoding neurobeachin-like 2). Genomic DNA sequencing confirmed mutations in NBEAL2 as the genetic cause of GPS. NBEAL2 encodes a protein containing a BEACH domain that is predicted to be involved in vesicular trafficking and may be critical for the development of platelet α-granules.

Figure 1

Abnormal sequence reads in NBEAL2 transcripts observed in platelet RNA from an individual with GPS. Snapshots shown from Integrated Genome Browser (IGB) for NBEAL2 transcripts expressed in platelets isolated from (top) a healthy donor and (bottom) an individual with GPS. Bar heights represent relative numbers of 50-base pair reads spanning NBEAL2; Refseq gene annotation for NBEAL2 is shown at the bottom. The red box outlines a region where introns are abnormally retained in NBEAL2 transcripts from platelets from the individual with GPS. See Supplementary Methods for details.

Figure 2

Mutation analysis of NBEAL2. (a) Pedigrees for three GPS-affected families with mutation status shown beneath symbols for each individual. (b) Schematic of NBEAL2, which is composed of 54 exons encoding untranslated regions (yellow) and protein-coding sequences (blue; the BEACH domain is encoded by exons 37–45). Red arrows indicate the locations of mutations in the NBEAL2 genomic sequence found in individuals with GPS (chromatograms are shown in Supplementary Fig. 3).