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Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci

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 architectur...

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Autores principales: Martínez‐Gil, Núria, Ovejero, Diana, Garcia‐Giralt, Natalia, Bruque, Carlos David, Mellibovsky, Leonardo, Nogués, Xavier, Rabionet, Raquel, Grinberg, Daniel, Balcells, Susanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009133/
https://www.ncbi.nlm.nih.gov/pubmed/35434450
http://dx.doi.org/10.1002/jbm4.10602
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author Martínez‐Gil, Núria
Ovejero, Diana
Garcia‐Giralt, Natalia
Bruque, Carlos David
Mellibovsky, Leonardo
Nogués, Xavier
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
author_facet Martínez‐Gil, Núria
Ovejero, Diana
Garcia‐Giralt, Natalia
Bruque, Carlos David
Mellibovsky, Leonardo
Nogués, Xavier
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
author_sort Martínez‐Gil, Núria
collection PubMed
description 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.
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spelling pubmed-90091332022-04-15 Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci Martínez‐Gil, Núria Ovejero, Diana Garcia‐Giralt, Natalia Bruque, Carlos David Mellibovsky, Leonardo Nogués, Xavier Rabionet, Raquel Grinberg, Daniel Balcells, Susanna JBMR Plus Original Articles 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. John Wiley & Sons, Inc. 2022-02-18 /pmc/articles/PMC9009133/ /pubmed/35434450 http://dx.doi.org/10.1002/jbm4.10602 Text en © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Martínez‐Gil, Núria
Ovejero, Diana
Garcia‐Giralt, Natalia
Bruque, Carlos David
Mellibovsky, Leonardo
Nogués, Xavier
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title_full Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title_fullStr Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title_full_unstemmed Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title_short Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci
title_sort genetic analysis in a familial case with high bone mineral density suggests additive effects at two loci
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009133/
https://www.ncbi.nlm.nih.gov/pubmed/35434450
http://dx.doi.org/10.1002/jbm4.10602
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