{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:44:42Z","timestamp":1789595082497,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,2,23]],"date-time":"2006-02-23T00:00:00Z","timestamp":1140652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2006,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Mutations in the <jats:italic>PITX2<\/jats:italic> homeobox gene are known to contribute to Axenfeld\u2010Rieger syndrome (ARS), an autosomal\u2010dominant developmental disorder. Although most mutations are in the homeodomain and result in a loss of function, there is a growing subset in the C\u2010terminal domain that has not yet been characterized. These mutations are of particular interest because the C\u2010terminus has both inhibitory and stimulatory activities.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>In this study we used a combination of in vitro DNA binding and transfection reporter assays to investigate the fundamental issue of whether C\u2010terminal mutations result in gain or loss of function at a cellular level.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We report a new frameshift mutation in the <jats:italic>PITX2<\/jats:italic> allele that predicts a truncated protein lacking most of the C\u2010terminal domain (D122FS). This newly reported mutant and another ARS C\u2010terminal mutant (W133Stop) both have greater binding than wild\u2010type to the bicoid element. Of interest, the mutants yielded \u223c5\u2010fold greater activation of the <jats:italic>prolactin<\/jats:italic> promoter in CHO cells, even though the truncated proteins were expressed at lower levels than the wild\u2010type protein. The truncated proteins also had greater than wild\u2010type activity in 2 other cell lines, including the LS8 oral epithelial line that expresses the endogenous <jats:italic>Pitx2<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The results indicate that the PITX2 C\u2010terminal domain has inhibitory activity and support the notion that ARS may also be caused by gain\u2010of\u2010function mutations. Birth Defects Research (Part A), 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.20226","type":"journal-article","created":{"date-parts":[[2006,2,23]],"date-time":"2006-02-23T19:46:34Z","timestamp":1140723994000},"page":"175-181","source":"Crossref","is-referenced-by-count":23,"title":["An unusual class of <i>PITX2<\/i> mutations in Axenfeld\u2010Rieger syndrome"],"prefix":"10.1002","volume":"76","author":[{"given":"Irfan","family":"Saadi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Toro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adisa","family":"Kuburas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Semina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey 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