title: Two genetic defects in alphaIIb are associated with type I Glanzmann's thrombasthenia in a Great Pyrenees dog: a 14-base insertion in exon 13 and a splicing defect of intron 13.
abstract: Glannzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by qualitative or quantitative deficiencies of the platelet membrane glycoprotein alphaIIbbeta3. This is the first report of a molecular genetic basis for type I GT in dogs. As previously reported, a thrombasthenic Great Pyrenees dog (dog No. 1) experienced uncontrolled epistaxis despite results of coagulation screening tests, platelet quantitation, and von Willebrand factor quantitation that were within reference ranges. Platelet aggregation was minimal in response to agonists. Flow cytometry, autoradiography, and immunoblot experiments demonstrated either marked reduction or absence of glycoproteins alphaIIb and beta3. In this study, we report the presence of a 14-base insertion in exon 13 and defective splicing of intron 13 in the alphaIIb gene of two thrombasthenic dogs (Nos. 1 and 8). The insertion disrupted the fourth alphaIIb calcium-binding domain, caused a shift in the reading frame and resulted in a premature termination codon. Possible consequences of this mutation include decreased alphaIIb mRNA stability and production of truncated alphaIIb protein that lacks the transmembrane and cytoplasmic domains and a large portion of the extracellular domain. We identified the dam, sire, and three littermates of dog No. 8 as carriers of the alphaIIb mutation. Canine alphaIIb and beta3 genes share significant homology with the genes in human beings, making canine GT an excellent translational model for human GT. A defined molecular basis for canine GT will enhance ongoing gene therapy research and increase the understanding of structure-function relationships of this integrin.
authors: Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849, USA. lipscdl@vetmed.auburn.edu
authors: D L
authors: DL
authors: Lipscomb
authors: C
authors: C
authors: Bourne
authors: M K
authors: MK
authors: Boudreaux
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005091:Exons; D005260:Female; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000662:veterinary; D017422:Sequence Analysis, DNA / Q000662:veterinary; D013915:Thrombasthenia / Q000235:genetics / Q000662:veterinary*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex