{"doi":"10.1101/2020.07.06.20143263","title":"A Sardinian founder mutation in <i>GP1BB</i> that impacts thrombocytopenia","abstract":"Abstract To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17×10 −16 ). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13×10 −10 ), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10 −8 ) and GPIX (−24.69%, P=2.66×10 −6 ). Molecular modeling infers a corresponding reduction in the stability of GP1BB. These observations predict that in homozygosity as well as in individuals carrying specific compound heterozygous configurations, this variant likely causes BSS.","journal":"medRxiv","year":2020,"id":130371,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":55363,"name":"Maristella Steri","orcid":"0000-0001-5869-3872","position":1,"is_corresponding":false},{"id":14664,"name":"Valeria Orrù","orcid":"0000-0002-6047-4625","position":2,"is_corresponding":false},{"id":218097,"name":"Gabriella Sole","orcid":"0000-0001-5292-5038","position":3,"is_corresponding":false},{"id":218096,"name":"Stefania Olla","orcid":"0000-0001-8735-671X","position":4,"is_corresponding":false},{"id":218094,"name":"Michele Marongiu","orcid":"0000-0002-7289-9815","position":5,"is_corresponding":false},{"id":218093,"name":"Carlo Sidore","orcid":"0000-0001-7504-7477","position":6,"is_corresponding":false},{"id":218098,"name":"Sandra Lai","orcid":"0000-0003-4198-9989","position":7,"is_corresponding":false},{"id":14663,"name":"Antonella Mulas","orcid":"0000-0002-6856-1483","position":8,"is_corresponding":false},{"id":70739,"name":"Andrea Maschio","orcid":"0000-0002-4238-9144","position":9,"is_corresponding":false},{"id":55374,"name":"Magdalena Żołędziewska","orcid":"0000-0002-3033-6133","position":10,"is_corresponding":false},{"id":218109,"name":"Matteo Floris","orcid":"0000-0003-4385-9336","position":11,"is_corresponding":false},{"id":582733,"name":"Mauro Pala","orcid":"0000-0002-4933-9182","position":12,"is_corresponding":false},{"id":533388,"name":"Paola Forabosco","orcid":"0000-0002-2006-2693","position":13,"is_corresponding":false},{"id":533389,"name":"Isadora Asunis","orcid":"0000-0002-4389-2470","position":14,"is_corresponding":false},{"id":218104,"name":"Maristella Pitzalis","orcid":"0000-0003-4975-6987","position":15,"is_corresponding":false},{"id":218105,"name":"Francesca Deidda","orcid":null,"position":16,"is_corresponding":false},{"id":533390,"name":"Marco Masala","orcid":"0000-0001-5556-9964","position":17,"is_corresponding":false},{"id":533391,"name":"Cristian Antonio Caria","orcid":"0000-0002-6806-3492","position":18,"is_corresponding":false},{"id":533392,"name":"Susanna Barella","orcid":"0000-0002-1952-7836","position":19,"is_corresponding":false},{"id":14736,"name":"Gonçalo R. 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