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

ABSTRACT: Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of ?-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.

SUBMITTER: Albers CA

PROVIDER: S-EPMC3428934 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Albers Cornelis A CA Cvejic Ana A Favier Rémi R Bouwmans Evelien E EE Alessi Marie-Christine MC Bertone Paul P Jordan Gregory G Kettleborough Ross N W RN Kiddle Graham G Kostadima Myrto M Read Randy J RJ Sipos Botond B Sivapalaratnam Suthesh S Smethurst Peter A PA Stephens Jonathan J Voss Katrin K Nurden Alan A Rendon Augusto A Nurden Paquita P Ouwehand Willem H WH

Nature genetics 20110717 8

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 abrogate ...[more]

PMID: 21765411

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

Project description: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 ?-granules.

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Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice.

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Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice.

Project description:During the analysis of a whole genome ENU mutagenesis screen for thrombosis modifiers, a spontaneous 8 base pair (bp) deletion causing a frameshift in exon 27 of the Nbeal2 gene was identified. Though initially considered as a plausible thrombosis modifier, this Nbeal2 mutation failed to suppress the synthetic lethal thrombosis on which the original ENU screen was based. Mutations in NBEAL2 cause Gray Platelet Syndrome (GPS), an autosomal recessive bleeding disorder characterized by macrothrombocytopenia and gray-appearing platelets due to lack of platelet alpha granules. Mice homozygous for the Nbeal2 8 bp deletion (Nbeal2gps/gps) exhibit a phenotype similar to human GPS, with significantly reduced platelet counts compared to littermate controls (p = 1.63 x 10-7). Nbeal2gps/gps mice also have markedly reduced numbers of platelet alpha granules and an increased level of emperipolesis, consistent with previously characterized mice carrying targeted Nbeal2 null alleles. These findings confirm previous reports, provide an additional mouse model for GPS, and highlight the potentially confounding effect of background spontaneous mutation events in well-characterized mouse strains.

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

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Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome.

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Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

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