{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T21:26:16Z","timestamp":1790976376958,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2003,9,17]],"date-time":"2003-09-17T00:00:00Z","timestamp":1063756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2003,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>SOX10<\/jats:italic> is a member of the <jats:italic>SOX<\/jats:italic> gene family related by homology to the high\u2010mobility group (HMG) box region of the testis\u2010determining gene <jats:italic>SRY<\/jats:italic>. Mutations of the transcription factor gene <jats:italic>SOX10<\/jats:italic> lead to Waardenburg\u2010Hirschsprung syndrome (Waardenburg\u2010Shah syndrome, WS4) in humans. A number of <jats:italic>SOX10<\/jats:italic> mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for <jats:italic>SOX10<\/jats:italic> have been identified. We have analyzed the impact of six different <jats:italic>SOX10<\/jats:italic> mutations on the activation of <jats:italic>SOX10<\/jats:italic> target genes by yeast one\u2010hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the <jats:italic>RET<\/jats:italic> promoter; and Sox10 binding sites identified in the <jats:italic>P0<\/jats:italic> promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the <jats:italic>SOX10<\/jats:italic> mutants appeared to correlate with the intestinal and\/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the <jats:italic>RET<\/jats:italic> promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the <jats:italic>P0<\/jats:italic> promoter. While the lack of normal SOX10 mediated activation of <jats:italic>RET<\/jats:italic> transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.10656","type":"journal-article","created":{"date-parts":[[2003,9,29]],"date-time":"2003-09-29T07:41:01Z","timestamp":1064821261000},"page":"573-585","source":"Crossref","is-referenced-by-count":45,"title":["Analysis of <i>SOX10<\/i> mutations identified in Waardenburg\u2010Hirschsprung patients: Differential effects on target gene regulation"],"prefix":"10.1002","volume":"90","author":[{"given":"Kwok Keung","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne Kung 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