title: Genetic deletion of mouse platelet glycoprotein Ibbeta produces a Bernard-Soulier phenotype with increased alpha-granule size.
abstract: Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ibbeta subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ibalpha subunit, GP Ibbeta(Null) mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ibbeta(Null) genotype revealed alpha-granules with increased size as compared with the alpha-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger alpha-granules in the GP Ibbeta(Null) platelet. The SEPT5 gene resides approximately 250 nucleotides 5' to the GP Ibbeta gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ibbeta coding sequences as a result in an imperfect polyadenylation signal within the 3' end of both the human and mouse SEPT5 genes. We observed a 2- to 3-fold increase in SEPT5 protein levels in platelets from GP Ibbeta(Null) mice. These results implicate SEPT5 levels in the maintenance of normal alpha-granule size and may explain the variant granules associated with human GP Ibbeta mutations and the Bernard-Soulier syndrome.
authors.affiliation: University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kato
authors.forename: Constantino
authors.initials: C
authors.lastname: Martinez
authors.forename: Susan
authors.initials: S
authors.lastname: Russell
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Alan
authors.initials: A
authors.lastname: Nurden
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
mesh_terms: D000818:Animals; D001606:Bernard-Soulier Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001760:Bleeding Time; D001772:Blood Cell Count; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D010641:Phenotype; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058112:Septins; D013623:Tail / Q000503:physiopathology
chemical_list: D018797:Cell Cycle Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D012333:RNA, Messenger; C491612:Sept5 protein, mouse; D058112:Septins