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1. αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum.

Author

Sara Morais, Jorge Oliveira, Catarina Lau, Mónica Pereira, Marta Gonçalves, Catarina Monteiro, Ana Rita Gonçalves, Rui Matos, Marco Sampaio, Eugénia Cruz, Inês Freitas, Rosário Santos, and Margarida Lima

Subjects
Medicine, Science
Abstract

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.

Published
2020
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2. αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

Author

Catarina Monteiro, Mónica Pereira, Marco Sampaio, Jorge Oliveira, Catarina Lau, Rosário Santos, Rui Matos, Inês Freitas, Margarida Lima, Marta Gonçalves, Ana R. Gonçalves, Sara Morais, and Eugénia Cruz

Subjects
Male, Integrins, Physiology, Protein Conformation, Integrin alpha2, Vascular Medicine, Biochemistry, Animal Cells, Medicine and Health Sciences, Electrochemistry, Missense mutation, Salt Bridges, Platelet, Genetics, Multidisciplinary, Integrin beta3, Hematology, Body Fluids, Extracellular Matrix, Chemistry, Transmembrane domain, Blood, Physical Sciences, Medicine, Female, Anatomy, Cellular Types, Cellular Structures and Organelles, Bacterial outer membrane, Research Article, Thrombasthenia, Platelets, Science, Autosomal dominant macrothrombocytopenia, Mutation, Missense, Hemorrhage, Platelet Glycoprotein GPIIb-IIIa Complex, Biology, Signs and Symptoms, Cell Adhesion, Humans, Platelet activation, Blood Coagulation, Gene, Blood Cells, Biology and Life Sciences, Proteins, Human Genetics, Cell Biology, Platelet Activation, Thrombocytopenia, Human genetics, Mutation, Clinical Medicine, Collagens
Abstract

BackgroundRare pathogenic variants in either theITGA2BorITGB3genes 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 theITGA2BorITGB3genes.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 inITGA2B(5 families), and 4 inITGB3(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 reportedITGA2BandITGB3variants 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.

Published
2020

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