{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:39:07Z","timestamp":1772156347844,"version":"3.50.1"},"posted":{"date-parts":[[2023,5,27]]},"group-title":"Genetics","reference-count":105,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,11,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the\n                  <jats:italic>PAX1<\/jats:italic>\n                  gene. Here we sought to define the roles of\n                  <jats:italic>PAX1<\/jats:italic>\n                  and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in\n                  <jats:italic>COL11A1<\/jats:italic>\n                  encoding collagen (\u03b11) XI (rs3753841; NM_080629.2_c.4004C&gt;T; p.(Pro1335Leu); P=7.07e\n                  <jats:sup>-11<\/jats:sup>\n                  , OR=1.118). Using CRISPR mutagenesis we generated\n                  <jats:italic>Pax1<\/jats:italic>\n                  knockout mice (\n                  <jats:italic>\n                    Pax1\n                    <jats:sup>-\/<\/jats:sup>\n                  <\/jats:italic>\n                  <jats:sup>-<\/jats:sup>\n                  ). In postnatal spines we found that PAX1 and collagen (\u03b11) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (\u03b11) XI detected in\n                  <jats:italic>\n                    Pax1\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  spines compared to wildtype. By genetic targeting we found that wildtype\n                  <jats:italic>Col11a1<\/jats:italic>\n                  expression in costal chondrocytes suppresses expression of\n                  <jats:italic>Pax1<\/jats:italic>\n                  and of\n                  <jats:italic>Mmp3<\/jats:italic>\n                  , encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated\n                  <jats:italic>COL11A1<\/jats:italic>\n                  <jats:sup>P1335L<\/jats:sup>\n                  mutant. Further, we found that either knockdown of the estrogen receptor gene\n                  <jats:italic>Esr2<\/jats:italic>\n                  , or tamoxifen treatment, significantly altered\n                  <jats:italic>Col11a1<\/jats:italic>\n                  and\n                  <jats:italic>Mmp3<\/jats:italic>\n                  expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a\n                  <jats:italic>Pax1<\/jats:italic>\n                  -\n                  <jats:italic>Col11a1<\/jats:italic>\n                  -\n                  <jats:italic>Mmp3<\/jats:italic>\n                  signaling axis in spinal chondrocytes.\n                <\/jats:p>","DOI":"10.1101\/2023.05.26.542293","type":"posted-content","created":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T01:55:10Z","timestamp":1685238910000},"source":"Crossref","is-referenced-by-count":1,"title":["Association of genetic variation in\n                  <i>COL11A1<\/i>\n                  with adolescent idiopathic scoliosis"],"prefix":"10.64898","author":[{"given":"Hao","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas M.","family":"Khanshour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aki","family":"Ushiki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nao","family":"Otomo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinao","family":"Koike","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet","family":"Einarsdottir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhui","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilian","family":"Antunes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yared H.","family":"Kidane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reuel","family":"Cornelia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rory","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimin","family":"Pei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick V.","family":"Grishin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bret M.","family":"Evers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason Pui Yin","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John A.","family":"Herring","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikashi","family":"Terao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"You-Qiang","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina A.","family":"Gurnett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Gerdhem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiro","family":"Ikegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan J.","family":"Rios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadav","family":"Ahituv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-2194","authenticated-orcid":false,"given":"Carol A.","family":"Wise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023112507100496000_2023.05.26.542293v3.1","unstructured":"Richards, B.S. , Sucato, D.J. , Johnston C.E. 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