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Loss\u2010of\u2010function mutations in\n                    <jats:italic>PAX9<\/jats:italic>\n                    and\n                    <jats:italic>WNT10A<\/jats:italic>\n                    have been known to cause FTA with various expressivity. In this study, we identified five FTA kindreds with novel\n                    <jats:italic>PAX9<\/jats:italic>\n                    disease\u2010causing mutations: p.(Glu7Lys), p.(Val83Leu), p.(Pro118Ser), p.(Ser197Argfs*23), and c.771+4A&gt;G. Concomitant\n                    <jats:italic>PAX9<\/jats:italic>\n                    and\n                    <jats:italic>WNT10A<\/jats:italic>\n                    pathogenic variants found in two probands with severe phenotypes suggested an effect of mutational synergism. All overexpressed PAX9s showed proper nuclear localization, excepting the p.(Pro118Ser) mutant. Various missense mutations caused differential loss of\n                    <jats:italic>PAX9<\/jats:italic>\n                    transcriptional ability.\n                    <jats:italic>PAX9<\/jats:italic>\n                    overexpression in dental pulp cells upregulated\n                    <jats:italic>LEF1<\/jats:italic>\n                    and\n                    <jats:italic>AXIN2<\/jats:italic>\n                    expression, indicating a positive regulatory role for PAX9 in canonical Wnt signaling. Analyzing 176 cases with 63 different mutations, we observed a distinct pattern of tooth agenesis for\n                    <jats:italic>PAX9<\/jats:italic>\n                    \u2010associated FTA: Maxillary teeth are in general more frequently affected than mandibular ones. Along with all second molars, maxillary bicuspids and first molars are mostly involved, while maxillary lateral incisors and mandibular bicuspids are relatively less affected. Genotypically, missense mutations are associated with fewer missing teeth than frameshift and nonsense variants. This study significantly expands the phenotypic and genotypic spectrums of\n                    <jats:italic>PAX9<\/jats:italic>\n                    \u2010associated disorders and reveals a molecular mechanism of genetic synergism underlying FTA variable expressivity.\n                  <\/jats:p>","DOI":"10.1111\/nyas.14988","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T01:18:00Z","timestamp":1680484680000},"page":"87-96","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["<i>PAX9<\/i>\n                    mutations and genetic synergism in familial tooth agenesis"],"prefix":"10.1111","volume":"1524","author":[{"given":"Kuan\u2010Yu","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"},{"name":"Department of Pediatric Dentistry National Taiwan University Children's Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin\u2010Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"},{"name":"Department of Pediatric Dentistry National Taiwan University Children's Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung\u2010Tsu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Hui","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung\u2010Chen Jane","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Jane","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan\u2010Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry National Taiwan University Children's Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Simmer","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.\u2010C.","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences 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