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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:p>\n                    Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous\n                    <jats:italic>Sox9<\/jats:italic>\n                    null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in\u00a0vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in\u00a0vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous\n                    <jats:italic>Sox9<\/jats:italic>\n                    null mutation (\n                    <jats:italic>Sox9<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) with the\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/Y440X<\/jats:sup>\n                    <\/jats:italic>\n                    CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/Y440X<\/jats:sup>\n                    <\/jats:italic>\n                    mice survived, all\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/Y440X<\/jats:sup>\n                    <\/jats:italic>\n                    compared with\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    . Activating\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>Y440X<\/jats:sup>\n                    <\/jats:italic>\n                    specifically in the chondrocyte\u2013osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing\n                    <jats:italic>\n                      Sox9\n                      <jats:sup>+\/Y440X<\/jats:sup>\n                    <\/jats:italic>\n                    limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9\n                    <jats:sup>Y440X<\/jats:sup>\n                    failed to interact with \u03b2-catenin and was unable to suppress transactivation of\n                    <jats:italic>Ihh<\/jats:italic>\n                    in cell-based assays\n                    <jats:italic>.<\/jats:italic>\n                    We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency\/hypomorphic and dominant-negative actions of SOX9\n                    <jats:sup>Y440X<\/jats:sup>\n                    , cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2208623119","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T15:14:01Z","timestamp":1672413241000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["Hypomorphic and dominant-negative impact of truncated SOX9 dysregulates Hedgehog\u2013Wnt signaling, causing campomelia"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4131-1951","authenticated-orcid":false,"given":"Tiffany Y. K.","family":"Au","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2698-7686","authenticated-orcid":false,"given":"Raymond K. H.","family":"Yip","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6531-8181","authenticated-orcid":false,"given":"Sarah L.","family":"Wynn","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8455-7778","authenticated-orcid":false,"given":"Tiong Y.","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9835-5018","authenticated-orcid":false,"given":"Alex","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, New Territories, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-0641","authenticated-orcid":false,"given":"Yu Hong","family":"Geng","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3925-1136","authenticated-orcid":false,"given":"Irene Y. 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