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Variants in\n                    <jats:italic>LRP5<\/jats:italic>\n                    were also described in osteoporosis pseudoglioma syndrome, combining severe osteoporosis and eye abnormalities. Genomewide\u2010association studies (GWAS) showed that\n                    <jats:italic>LRP5<\/jats:italic>\n                    p.Val667Met (V667M) variant is associated with low bone mineral density (BMD) and increased fractures. However, despite association with a bone phenotype in humans and knockout mice, the impact of the variant in bone and eye remains to be investigated. Here, we aimed to evaluate the bone and ocular impact of the V667M variant. We recruited 11 patients carrying the V667M variant or other loss\u2010of\u2010function variants of\n                    <jats:italic>LRP5<\/jats:italic>\n                    and generated an\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    mutated mice. Patients had low lumbar and hip BMD\n                    <jats:italic>Z<\/jats:italic>\n                    \u2010score and altered bone microarchitecture evaluated by HR\u2010pQCT compared with an age\u2010matched reference population. Murine primary osteoblasts from\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    mice showed lower differentiation capacity, alkaline phosphatase activity, and mineralization capacity in vitro. Ex vivo, mRNA expression of\n                    <jats:italic>Osx<\/jats:italic>\n                    ,\n                    <jats:italic>Col1<\/jats:italic>\n                    , and\n                    <jats:italic>osteocalcin<\/jats:italic>\n                    was lower in\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    bones than controls (all\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01).\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    3\u2010month\u2010old mice, compared with control (CTL) mice, had decreased BMD at the femur (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) and lumbar spine (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) with normal microarchitecture and bone biomarkers. However,\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    mice revealed a trend toward a lower femoral and vertebral stiffness (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.14) and had a lower hydroxyproline\/proline ratio compared with CTL, (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01), showing altered composition and quality of the bone matrix. Finally, higher tortuosity of retinal vessels was found in the\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    mice and unspecific vascular tortuosity in two patients only. In conclusion,\n                    <jats:italic>Lrp5<\/jats:italic>\n                    <jats:sup>V667M<\/jats:sup>\n                    variant is associated with low BMD and impaired bone matrix quality. Retinal vascularization abnormalities were observed in mice. \u00a9 2023 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10741","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T08:54:36Z","timestamp":1678870476000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>\n                      <i>Lrp5<\/i>\n                    <\/scp>\n                    p.\n                    <scp>Val667Met<\/scp>\n                    Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis"],"prefix":"10.1093","volume":"7","author":[{"given":"St\u00e9phanie","family":"Fabre","sequence":"first","affiliation":[{"name":"INSERM U1132 Bioscar Universit\u00e9 de Paris Cit\u00e9  Paris 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