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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,13]]},"abstract":"<jats:p>\n                    Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the\n                    <jats:italic>LRP1<\/jats:italic>\n                    (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the\n                    <jats:italic>LRP1<\/jats:italic>\n                    variants presented a typical DDH phenotype. The heterozygous\n                    <jats:italic>Lrp1<\/jats:italic>\n                    knockout (KO) mouse (\n                    <jats:italic>Lrp1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) showed phenotypes recapitulating the human DDH phenotypes, indicating\n                    <jats:italic>Lrp1<\/jats:italic>\n                    loss of function causes DDH.\n                    <jats:italic>Lrp1<\/jats:italic>\n                    knockin mice with a missense variant corresponding to a human variant identified in DDH (\n                    <jats:italic>\n                      Lrp1\n                      <jats:sup>R1783W<\/jats:sup>\n                    <\/jats:italic>\n                    ) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the\n                    <jats:italic>Lrp1<\/jats:italic>\n                    KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore,\n                    <jats:italic>Lrp1<\/jats:italic>\n                    deficiency caused a significant decrease of chondrogenic ability in\u00a0vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant \u03b2-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a \u03b2-catenin antagonist) in an shRNA-Lrp1\u2013expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2203557119","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T13:57:56Z","timestamp":1662472676000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2271-4894","authenticated-orcid":false,"given":"Wenjin","family":"Yan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing 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