title: Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Kärt
authors.initials: K
authors.lastname: Tomberg
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Rami
authors.initials: R
authors.lastname: Khoriaty
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, Michigan, United States of America.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Westrick
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Fairfield
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Reinholdt
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Brodsky
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Pavel
authors.initials: P
authors.lastname: Davizon-Castillo
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.|Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.|Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America.|Human Medical Genetics and Genomics Program, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Di Paola
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020029:Base Pairing / Q000235:genetics*; D001483:Base Sequence; D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics*; D001853:Bone Marrow / Q000276:immunology; D057687:Emperipolesis / Q000235:genetics; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D016368:Frameshift Mutation; D055652:Gray Platelet Syndrome / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009503:Neutropenia / Q000150:complications; D009504:Neutrophils / Q000166:cytology; D013154:Spleen / Q000276:immunology; D013921:Thrombocytopenia / Q000150:complications
chemical_list: D001798:Blood Proteins; C585423:Nbeal2 protein, mouse