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dc.contributor.authorGregson, Celia Len
dc.contributor.authorWheeler, Lawrieen
dc.contributor.authorHardcastle, Sarah Aen
dc.contributor.authorAppleton, Louise Hen
dc.contributor.authorAddison, Kathryn Aen
dc.contributor.authorBrugmans, Mariekeen
dc.contributor.authorClark, Graemeen
dc.contributor.authorWard, Kate Aen
dc.contributor.authorPaggiosi, Margareten
dc.contributor.authorStone, Mikeen
dc.contributor.authorThomas, Joegien
dc.contributor.authorAgarwal, Rohanen
dc.contributor.authorPoole, Kennethen
dc.contributor.authorMcCloskey, Eugeneen
dc.contributor.authorFraser, William Den
dc.contributor.authorWilliams, Eleanoren
dc.contributor.authorBullock, Alex Nen
dc.contributor.authorSmith, George Daveyen
dc.contributor.authorBrown, Matthew Aen
dc.contributor.authorTobias, Jon Hen
dc.contributor.authorDuncan, Emma Len
dc.identifier.citationGregson et al. Journal of Bone and Mineral Research (2015) Vol. 31, Issue 3, pp. 640-649. doi: 10.1002/jbmr.2706en
dc.description.abstractHigh bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3′). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. © 2015 American Society for Bone and Mineral Research.
dc.description.sponsorshipThis study was supported by The Wellcome Trust and NIHR CRN (portfolio number 5163). CLG was funded by a Wellcome Trust Clinical Research Training Fellowship (080280/Z/06/Z), the EU 7th Framework Programme under grant agreement number 247642 (GEoCoDE), a British Geriatric Society travel grant, and is now funded by Arthritis Research UK (grant ref 20000). SH acknowledges Arthritis Research UK support (grant ref 19580). KESP acknowledges the support of Cambridge NIHR Biomedical Research Centre. KAW is supported by the core programme of the MRC Nutrition and Bone Health group at MRC Human Nutrition Research, funded by the UK Medical Research Council (Grant code U10590371). EM acknowledges support of the Sheffield Teaching Hospitals Foundation Trust Clinical Research Facility. The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Genome Canada (Ontario Genomics Institute OGI- 055), GlaxoSmithKline, Janssen, Lilly Canada, Novartis Research Foundation, Ontario Ministry of Economic Development & Innovation, Pfizer, Takeda, and Wellcome Trust (092809/Z/10/Z).
dc.rightsCreative Commons Attribution 4.0
dc.subjectprotein modelingen
dc.titleMutations in known monogenic High Bone Mass loci only explain a small proportion of High Bone Mass casesen
dc.description.versionThis is the final version of the article. It first appeared from Wiley via
prism.publicationNameJournal of Bone and Mineral Researchen
dc.rioxxterms.funderWellcome Trust
dc.contributor.orcidPoole, Kenneth [0000-0003-4546-7352]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)

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Creative Commons Attribution 4.0
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