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Article: Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation

TitleAnalysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation
Authors
KeywordsHMG domain
Intestinal aganglionosis
Neural crest
P0
RET
SOX10
Waardenburg-Hirschsprung syndrome
Issue Date2003
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/35503
Citation
Journal Of Cellular Biochemistry, 2003, v. 90 n. 3, p. 573-585 How to Cite?
AbstractSOX10 is a member of the SOXgene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 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 SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid 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 RET promoter; and Sox10 binding sites identified in the P0 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 SOX10 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 RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET 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. © 2003 Wiley-Liss, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/68061
ISSN
2015 Impact Factor: 3.446
2015 SCImago Journal Rankings: 1.520
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChan, KKen_HK
dc.contributor.authorWong, CKYen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorSham, MHen_HK
dc.date.accessioned2010-09-06T06:00:58Z-
dc.date.available2010-09-06T06:00:58Z-
dc.date.issued2003en_HK
dc.identifier.citationJournal Of Cellular Biochemistry, 2003, v. 90 n. 3, p. 573-585en_HK
dc.identifier.issn0730-2312en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68061-
dc.description.abstractSOX10 is a member of the SOXgene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 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 SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid 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 RET promoter; and Sox10 binding sites identified in the P0 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 SOX10 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 RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET 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. © 2003 Wiley-Liss, Inc.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/35503en_HK
dc.relation.ispartofJournal of Cellular Biochemistryen_HK
dc.rightsJournal of Cellular Biochemistry. Copyright © John Wiley & Sons, Inc.en_HK
dc.subjectHMG domainen_HK
dc.subjectIntestinal aganglionosisen_HK
dc.subjectNeural cresten_HK
dc.subjectP0en_HK
dc.subjectRETen_HK
dc.subjectSOX10en_HK
dc.subjectWaardenburg-Hirschsprung syndromeen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCells, Cultureden_HK
dc.subject.meshCloning, Molecularen_HK
dc.subject.meshDNA-Binding Proteins - geneticsen_HK
dc.subject.meshGene Expression Regulation - geneticsen_HK
dc.subject.meshHigh Mobility Group Proteins - geneticsen_HK
dc.subject.meshHirschsprung Disease - geneticsen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMutationen_HK
dc.subject.meshNIH 3T3 Cellsen_HK
dc.subject.meshPromoter Regions, Genetic - geneticsen_HK
dc.subject.meshRatsen_HK
dc.subject.meshSOXE Transcription Factorsen_HK
dc.subject.meshTranscription Factors - geneticsen_HK
dc.subject.meshTwo-Hybrid System Techniquesen_HK
dc.subject.meshWaardenburg's Syndrome - geneticsen_HK
dc.subject.meshYeasts - geneticsen_HK
dc.titleAnalysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0730-2312&volume=90&issue=3&spage=573&epage=585&date=2003&atitle=Analysis+of+SOX10+mutations+identified+in+Waardenburg-Hirschsprung+patients:+differential+effects+on+target+gene+regulationen_HK
dc.identifier.emailLui, VCH: vchlui@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.emailSham, MH: mhsham@hkucc.hku.hken_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.identifier.authoritySham, MH=rp00380en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/jcb.10656en_HK
dc.identifier.pmid14523991-
dc.identifier.scopuseid_2-s2.0-0141988843en_HK
dc.identifier.hkuros87755en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0141988843&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume90en_HK
dc.identifier.issue3en_HK
dc.identifier.spage573en_HK
dc.identifier.epage585en_HK
dc.identifier.isiWOS:000185766000015-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridChan, KK=7406034649en_HK
dc.identifier.scopusauthoridWong, CKY=36862867100en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridSham, MH=7003729109en_HK

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