{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T10:36:07Z","timestamp":1787999767567,"version":"build-2784847793"},"reference-count":49,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,4,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Gain-of-function (GOF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIb\u03b1 to von Willebrand factor (VWF) interaction, and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of the VWF-binding domain of GPIb\u03b1 and 1 in the macroglycopeptide. GOF GP1BA variants generate a high-affinity conformation of the C-terminal disulfide loop with a consequent allosteric conformational change on another region of GPIb\u03b1, the leucine-rich-repeat (LRR) domain. We identified a novel GP1BA variant (p.Arg127Gln) affecting the LRR5 domain of GPIb\u03b1 in a boy with easy bruising and laboratory test results suggestive of PT-VWD. We thus aimed to investigate the impact of the p.Arg127Gln variant on GPIb\u03b1 affinity for VWF and GPIb\u03b1 structure. Chinese hamster ovary cells expressing p.Arg127Gln GPIb\u03b1 showed increased binding of VWF induced by ristocetin and enhanced tethering on immobilized VWF as compared with cells expressing wild-type GPIb\u03b1. Surface plasmon resonance confirmed that p.Arg127Gln enhances the binding affinity of GPIb\u03b1 for VWF. Hydrogen-deuterium exchange mass spectrometry showed that p.Arg127Gln of LRR, while having little effect on the dynamics of the LRR locally, enhances the conformational dynamics of the GPIb\u03b1 C-terminal disulfide loop structure. Our data demonstrate for the first time that GOF variants outside the GPIb\u03b1 C-terminal disulfide loop may be pathogenic and that aminoacidic changes in the LRR may cause allosterically conformational changes in the C-terminal disulfide loop of GPIb\u03b1, inducing a conformation with high affinity for VWF.<\/jats:p>","DOI":"10.1182\/bloodadvances.2021005463","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:39:17Z","timestamp":1633653557000},"page":"2236-2246","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":15,"title":["A p.Arg127Gln variant in GPIb\u03b1 LRR5 allosterically enhances affinity for VWF: a novel form of platelet-type VWD"],"prefix":"10.1182","volume":"6","author":[{"given":"Loredana","family":"Bury","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy; 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8966-7367","authenticated-orcid":false,"given":"Giuseppe","family":"Guglielmini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Tischer","sequence":"additional","affiliation":[{"name":"Division of Hematology, Departments of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Moon-Tasson","sequence":"additional","affiliation":[{"name":"Division of Hematology, Departments of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, 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