Dataset Information

Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

ABSTRACT: The von Willebrand receptor complex, which is composed of the glycoproteins Ib?, Ib?, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.

SUBMITTER: Sivapalaratnam S

PROVIDER: S-EPMC6037295 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

Sivapalaratnam Suthesh S Westbury Sarah K SK Stephens Jonathan C JC Greene Daniel D Downes Kate K Kelly Anne M AM Lentaigne Claire C Astle William J WJ Huizinga Eric G EG Nurden Paquita P Papadia Sofia S Peerlinck Kathelijne K Penkett Christopher J CJ Perry David J DJ Roughley Catherine C Simeoni Ilenia I Stirrups Kathleen K Hart Daniel P DP Tait R Campbell RC Mumford Andrew D AD Laffan Michael A MA Freson Kathleen K Ouwehand Willem H WH Kunishima Shinji S Turro Ernest E

Blood 20161114 4

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothr ...[more]

PMID: 28064200

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Project description:BackgroundRare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia.ObjectivesTo describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes.MethodsWe reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects.ResultsPatients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity.ConclusionsPreviously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

Dataset Information

Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

Publications

Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

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