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Genetic analysis in a familial case with high bone mineral density suggests additive effects at two loci

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dc.contributor.author Martínez-Gil, Núria
dc.contributor.author Ovejero Crespo, Diana
dc.contributor.author Garcia Giralt, Natàlia
dc.contributor.author Bruque, Carlos David
dc.contributor.author Mellibovsky, Leonardo
dc.contributor.author Nogués Solan, Francesc Xavier
dc.contributor.author Rabionet, Raquel
dc.contributor.author Grinberg, Daniel
dc.contributor.author Balcells, Susana
dc.date.accessioned 2022-09-28T06:15:23Z
dc.date.available 2022-09-28T06:15:23Z
dc.date.issued 2022
dc.identifier.citation Martínez-Gil N, Ovejero D, Garcia-Giralt N, Bruque CD, Mellibovsky L, Nogués X, Rabionet R, Grinberg D, Balcells S. Genetic analysis in a familial case with high bone mineral density suggests additive effects at two loci. JBMR Plus. 2022 Feb 18;6(4):e10602. DOI: 10.1002/jbm4.10602
dc.identifier.issn 2473-4039
dc.identifier.uri http://hdl.handle.net/10230/54182
dc.description.abstract Osteoporosis is the most common bone disease, characterized by a low bone mineral density (BMD) and increased risk of fracture. At the other end of the BMD spectrum, some individuals present strong, fracture-resistant, bones. Both osteoporosis and high BMD are heritable and their genetic architecture encompasses polygenic inheritance of common variants and some cases of monogenic highly penetrant variants in causal genes. We have investigated the genetics of high BMD in a family segregating this trait in an apparently Mendelian dominant pattern. We searched for rare causal variants by whole-exome sequencing in three affected and three nonaffected family members. Using this approach, we have identified 38 rare coding variants present in the proband and absent in the three individuals with normal BMD. Although we have found four variants shared by the three affected members of the family, we have not been able to relate any of these to the high-BMD phenotype. In contrast, we have identified missense variants in two genes, VAV3 and ADGRE5, each shared by two of out of three affected members, whose loss of function fits with the phenotype of the family. In particular, the proband, a woman displaying the highest BMD (sum Z-score = 7), carries both variants, whereas the other two affected members carry one each. VAV3 encodes a guanine-nucleotide-exchange factor with an important role in osteoclast activation and function. Although no previous cases of VAV3 mutations have been reported in humans, Vav3 knockout (KO) mice display dense bones, similarly to the high-BMD phenotype present in our family. The ADGRE5 gene encodes an adhesion G protein-coupled receptor expressed in osteoclasts whose KO mouse displays increased trabecular bone volume. Combined, these mouse and human data highlight VAV3 and ADGRE5 as novel putative high-BMD genes with additive effects, and potential therapeutic targets for osteoporosis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
dc.description.sponsorship Funds for the study include grants SAF2016-75948-R (Spanish MINECO), PID2019-107188RB-C21 (MICINN) and CIBERER (U720), CIBERFES (CB16/10/00245), and European Regional Development Fund for the whole project. We thank Mónica Cózar for technical assistance and the family for their enthusiastic participation.Authors' roles: NMG was involved in conceptualization, data curation, formal analysis, investigation, methodology, writing-original draft, and review & editing. CDB was involved in data curation, formal analysis, methodology, and review & editing. RR, DG, and SB were involved in conceptualization, funding acquisition, investigation, supervision, writing-original draft, and review & editing. DO and NGG were involved in investigation, data curation, and writing-review & editing. XN and LM were involved in conceptualization, data curation, and writing-review & editing.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof JBMR Plus. 2022 Feb 18;6(4):e10602
dc.rights © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Genetic analysis in a familial case with high bone mineral density suggests additive effects at two loci
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1002/jbm4.10602
dc.subject.keyword Diseases and disorders of/related to bone
dc.subject.keyword Genetic research
dc.subject.keyword Molecular pathways‐remodeling
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75948-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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