{"doi":"10.1111/bjh.16479","title":"High prevalence of the natural Asn89Asp mutation in the <i>GP1BB</i> gene associated with Bernard–Soulier syndrome in French patients from the genetic isolate of Reunion Island","abstract":"Congenital defects in the platelet GPIb-IX-V complex result in quantitative deficiencies and cause the Bernard–Soulier syndrome (BSS) bleeding disorder (Nurden & Nurden, 2011). BSS is an autosomal recessive disease characterised by moderate to severe thrombocytopaenia, giant platelets and mucocutaneous bleedings (Lanza, 2006). Mutations in any one of the three genes GP1BA, GP1BB or GP9 may lead to impaired expression of the GPIb-IX-V complex. The prevalence of BSS has been estimated at less than one in a million live births, but higher frequencies have been observed in particular regions. The island of Reunion is a French overseas territory where isolation from the mainland resulted in founder effects observed for different inherited diseases (Rodius et al., 1994; Richard et al., 1995). Occurrence of BSS has been known for several years in a number of patients referring to the main hospitals of Reunion Island. In each case, these patients were analysed for genetic defects in the GP1BA, GP1BB and GP9 genes. Sequencing of the GP1BB coding region revealed a similar homozygous c.265A>G transition in the 13 affected individuals. This mutation predicts a p.Asn89Asp amino acid change in GPIbβ. Analysis of seven relatives from five families showed that they were all heterozygous for the same mutation (Figure S1 and Table SI). The Asn to Asp change falls within the C-terminal region flanking the single LRR (leucine rich repeat) motif of GPIbβ. Alignment of corresponding sequences from other species revealed that the Asn mutated in the patient is highly conserved (Figure S2A). As shown in the 3D-model, the side chain of the Asn forms six close-knit hydrogen bonds with polar backbone atoms (Figure S2B) (McEwan et al., 2011). The mutation will replace the carboxamide group with a carboxylate, and although the change is relatively small, it will likely perturb the intricate hydrogen bond network around this residue. Therefore, the mutation is expected to be quite destabilising. In 2003, Strassel et al. reported a homozygous p.Asn89Thr substitution in a BSS patient and showed that this single amino acid substitution in the extracellular domain of GPIbβ affects the expression of both GPIbα and GPIX in transfected CHO cell lines. As illustrated in the Western Blot (WB) analysis of one patient (BSS1), GPIbα, GPIbβ and GPIX subunits, which are probably not correctly associated, were easily degraded leaving only trace amounts or absence of them in platelet lysates (Figure S3). Characteristics of the population study are described in Table SI. In total, 13 homozygous patients and 11 heterozygous carriers were included. In the group of BSS patients, median age at diagnosis was eight years (range 0–53 years), and seven patients (54%) had a late diagnosis after the age of seven (Fig 1A). In thrombocytopaenic heterozygous patients (6/11), the diagnosis of inherited thrombocytopaenia was realised at a very late stage (median ± SD = 42·5 ± 13 years). Among reasons for diagnostic delay, inherited thrombocytopaenia may be mistaken for or misdiagnosed as immune thrombocytopaenia (ITP). Indeed, 38% of BSS patients were misdiagnosed as having ITP and received treatment for this reason. Furthermore, three patients were splenectomised without benefit. The study of Savoia et al. (2011) also showed that four out of 13 BSS patients (31%) had an erroneous diagnosis of autoimmune thrombocytopaenia, treated with intravenous immunoglobulins, steroids and/or splenectomy. Among heterozygous carriers, at least one patient was misdiagnosed as having ITP, but did not receive any treatment. A detailed bleeding history for each patient is also reported in Table SI. Bleeding diathesis was variable and severity ranged from 5 to 22 (median ± SD = 11 ± 4·6) in BSS patients according to the ISTH-BAT (International Society of Thrombosis and Haemostasis Bleeding Assessment Tool) (Fig 1B). All menstruating women (5/8 patients) had menorrhagia that required, in 60% of them, estropr","journal":"British Journal of Haematology","year":2020,"id":111603,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"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":529852,"name":"Céline de Thoré","orcid":null,"position":1,"is_corresponding":false},{"id":529853,"name":"Hanitra Randrianaivo‐Ranjatoelina","orcid":null,"position":2,"is_corresponding":false},{"id":529854,"name":"Marie‐Jeanne Baas","orcid":null,"position":3,"is_corresponding":false},{"id":529855,"name":"Marie‐Line Jacquemont","orcid":null,"position":4,"is_corresponding":false},{"id":529856,"name":"Marie Dreyfus","orcid":null,"position":5,"is_corresponding":false},{"id":529052,"name":"Cécile Lavenu‐Bombled","orcid":"0000-0002-4860-8395","position":6,"is_corresponding":false},{"id":471258,"name":"Renhao Li","orcid":"0000-0002-5806-5080","position":7,"is_corresponding":false},{"id":241122,"name":"Christian Gachet","orcid":"0000-0003-1303-4210","position":8,"is_corresponding":false},{"id":529053,"name":"Arnaud Dupuis","orcid":"0000-0001-9058-7295","position":9,"is_corresponding":false},{"id":471257,"name":"François Lanza","orcid":"0000-0002-5802-4748","position":10,"is_corresponding":false},{"id":293052,"name":"Mathieu Fiore","orcid":"0000-0002-2526-8826","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-18T23:13:05.597252Z","pmid":"31997307","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}