{"id":576,"date":"2022-02-18T14:14:00","date_gmt":"2022-02-18T14:14:00","guid":{"rendered":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576"},"modified":"2023-11-03T14:18:28","modified_gmt":"2023-11-03T14:18:28","slug":"genetic-analysis-in-a-familial-case-with-high-bonemineral-density-suggests-additive-effects-at-two-loci","status":"publish","type":"post","link":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576","title":{"rendered":"Genetic Analysis in a Familial Case With High BoneMineral Density Suggests Additive Effects at Two Loci"},"content":{"rendered":"\n<p>N\u00faria Mart\u00ednez-Gil, Diana Ovejero, Natalia Garcia-Giralt, Carlos David Bruque, Leonardo Mellibovsky, Xavier Nogu\u00e9s, Raquel Rabionet, Daniel Grinberg, and Susanna Balcells<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Abstract<\/h2>\n\n\n\n<p>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,\u00a0<em>VAV3<\/em>\u00a0and\u00a0<em>ADGRE5<\/em>, 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\u00a0<em>Z<\/em>-score = 7), carries both variants, whereas the other two affected members carry one each.\u00a0<em>VAV3<\/em>\u00a0encodes a guanine-nucleotide-exchange factor with an important role in osteoclast activation and function. Although no previous cases of\u00a0<em>VAV3<\/em>\u00a0mutations have been reported in humans,\u00a0<em>Vav3<\/em>\u00a0knockout (KO) mice display dense bones, similarly to the high-BMD phenotype present in our family. The\u00a0<em>ADGRE5<\/em>\u00a0gene 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\u00a0<em>VAV3<\/em>\u00a0and\u00a0<em>ADGRE5<\/em>\u00a0as novel putative high-BMD genes with additive effects, and potential therapeutic targets for osteoporosis. \u00a9 2022 The Authors.\u00a0<em>JBMR Plus<\/em>\u00a0published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.<\/p>\n\n\n\n<div class=\"wp-block-buttons is-layout-flex wp-block-buttons-is-layout-flex\">\n<div class=\"wp-block-button has-custom-width wp-block-button__width-100\"><a class=\"wp-block-button__link wp-element-button\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/35434450\/\" target=\"_blank\" rel=\"noreferrer noopener\">Ver Publicaci\u00f3n<\/a><\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>N\u00faria Mart\u00ednez-Gil, Diana Ovejero, Natalia Garcia-Giralt, Carlos David Bruque, Leonardo Mellibovsky, Xavier Nogu\u00e9s, Raquel Rabionet, Daniel Grinberg, and Susanna Balcells 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. [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":517,"comment_status":"closed","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"_eb_attr":"","_uag_custom_page_level_css":"","advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[11],"tags":[],"class_list":["post-576","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publicaciones"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v23.3 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Genetic Analysis in a Familial Case With High BoneMineral Density Suggests Additive Effects at Two Loci - UCT HP<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\" \/>\n<meta property=\"og:locale\" content=\"es_ES\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Genetic Analysis in a Familial Case With High BoneMineral Density Suggests Additive Effects at Two Loci - UCT HP\" \/>\n<meta property=\"og:description\" content=\"N\u00faria Mart\u00ednez-Gil, Diana Ovejero, Natalia Garcia-Giralt, Carlos David Bruque, Leonardo Mellibovsky, Xavier Nogu\u00e9s, Raquel Rabionet, Daniel Grinberg, and Susanna Balcells 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. [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\" \/>\n<meta property=\"og:site_name\" content=\"UCT HP\" \/>\n<meta property=\"article:published_time\" content=\"2022-02-18T14:14:00+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2023-11-03T14:18:28+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/wp-content\/uploads\/2023\/10\/wiley.png\" \/>\n\t<meta property=\"og:image:width\" content=\"250\" \/>\n\t<meta property=\"og:image:height\" content=\"200\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/png\" \/>\n<meta name=\"author\" content=\"Mirtha\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Escrito por\" \/>\n\t<meta name=\"twitter:data1\" content=\"Mirtha\" \/>\n\t<meta name=\"twitter:label2\" content=\"Tiempo de lectura\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutos\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576#article\",\"isPartOf\":{\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\"},\"author\":{\"name\":\"Mirtha\",\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/#\/schema\/person\/cb3d81609139435146e1257936dc9b98\"},\"headline\":\"Genetic Analysis in a Familial Case With High BoneMineral Density Suggests Additive Effects at Two Loci\",\"datePublished\":\"2022-02-18T14:14:00+00:00\",\"dateModified\":\"2023-11-03T14:18:28+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\"},\"wordCount\":356,\"publisher\":{\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/#organization\"},\"image\":{\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576#primaryimage\"},\"thumbnailUrl\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/wp-content\/uploads\/2023\/10\/wiley.png\",\"articleSection\":[\"publicaciones\"],\"inLanguage\":\"es\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\",\"url\":\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?p=576\",\"name\":\"Genetic Analysis in a Familial Case With High BoneMineral Density Suggests Additive Effects at Two Loci - 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At the other end of the BMD spectrum, some individuals present strong, fracture-resistant, bones. 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At the other end of the BMD spectrum, some individuals present strong, fracture-resistant, bones.&hellip;","coauthors":[],"tax_additional":{"categories":{"linked":["<a href=\"https:\/\/ucthp.hospitalelcalafate.gob.ar\/?cat=11\" class=\"advgb-post-tax-term\">publicaciones<\/a>"],"unlinked":["<span class=\"advgb-post-tax-term\">publicaciones<\/span>"]}},"comment_count":"0","relative_dates":{"created":"Publicado 4 a\u00f1os hace","modified":"Actualizado 3 a\u00f1os hace"},"absolute_dates":{"created":"Publicado el 18 de febrero de 2022","modified":"Actualizado el 3 de noviembre de 2023"},"absolute_dates_time":{"created":"Publicado el 18 de febrero de 2022 2:14 pm","modified":"Actualizado el 3 de noviembre de 2023 2:18 pm"},"featured_img_caption":"","series_order":"","_links":{"self":[{"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/posts\/576","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=576"}],"version-history":[{"count":1,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/posts\/576\/revisions"}],"predecessor-version":[{"id":577,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/posts\/576\/revisions\/577"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=\/wp\/v2\/media\/517"}],"wp:attachment":[{"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=576"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=576"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ucthp.hospitalelcalafate.gob.ar\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=576"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}