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Conference Paper: Insights into the function of SOX9 and campomelic dysplasia

TitleInsights into the function of SOX9 and campomelic dysplasia
Authors
Issue Date2008
PublisherAmerican Society for Matrix Biology
Citation
American Society for Matrix Biology 2008 Meeting, San Diego, CA, 7-10 December 2008 How to Cite?
AbstractHuman SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation. Studies in zebrafish and Xenopus suggest that Sox9 may be crucial for specification of the otic placode. In mice, loss of Sox9 results in failure of otic placode invagination. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a later morphogenetic role but phenotypic details are limited. Sox9-/- null mice die before morphogenesis of the inner ear is complete, precluding investigation of the role of Sox9 later in ear development. Because all the SOX9 mutations are heterozygous and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act dominant negatively by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. To assess whether such mutations in SOX9 may act via a dominant interference mechanism we generated transgenic and conditional knock’in mice expressing a mouse equivalent of a CD mutation, a Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). Our data reveal an essential role for Sox9 for sensory and non-sensory morphogenesis of the inner ear. We compared the phenotypic impact of the Sox9 Y440X mutation with a Sox9 null mutation. These studies point to context dependent mechanisms for the Y440X nonsense mutation.
Persistent Identifierhttp://hdl.handle.net/10722/61541

 

DC FieldValueLanguage
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorAu, YKen_HK
dc.contributor.authorSzeto, YYen_HK
dc.contributor.authorWynn, SLen_HK
dc.contributor.authorChan, YSen_HK
dc.contributor.authorCheung, KMCen_HK
dc.contributor.authorChan, WYen_HK
dc.contributor.authorLovell-Badge, RHen_HK
dc.contributor.authorFritzsch, Ben_HK
dc.date.accessioned2010-07-13T03:42:02Z-
dc.date.available2010-07-13T03:42:02Z-
dc.date.issued2008en_HK
dc.identifier.citationAmerican Society for Matrix Biology 2008 Meeting, San Diego, CA, 7-10 December 2008-
dc.identifier.urihttp://hdl.handle.net/10722/61541-
dc.description.abstractHuman SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation. Studies in zebrafish and Xenopus suggest that Sox9 may be crucial for specification of the otic placode. In mice, loss of Sox9 results in failure of otic placode invagination. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a later morphogenetic role but phenotypic details are limited. Sox9-/- null mice die before morphogenesis of the inner ear is complete, precluding investigation of the role of Sox9 later in ear development. Because all the SOX9 mutations are heterozygous and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act dominant negatively by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. To assess whether such mutations in SOX9 may act via a dominant interference mechanism we generated transgenic and conditional knock’in mice expressing a mouse equivalent of a CD mutation, a Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). Our data reveal an essential role for Sox9 for sensory and non-sensory morphogenesis of the inner ear. We compared the phenotypic impact of the Sox9 Y440X mutation with a Sox9 null mutation. These studies point to context dependent mechanisms for the Y440X nonsense mutation.-
dc.languageengen_HK
dc.publisherAmerican Society for Matrix Biology-
dc.relation.ispartofBiennial Meeting of the American Society for Matrix Biology-
dc.titleInsights into the function of SOX9 and campomelic dysplasiaen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailCheah, KSE: hrmbdkc@hkusua.hku.hken_HK
dc.identifier.emailAu, YK: h0294066@hkusua.hku.hken_HK
dc.identifier.emailSzeto, YY: yukyeeszeto@yahoo.com.hken_HK
dc.identifier.emailChan, YS: yschan@hkucc.hku.hken_HK
dc.identifier.emailCheung, KMC: cheungmc@hku.hken_HK
dc.identifier.emailChan, WY: torichan@gmail.comen_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityChan, YS=rp00318en_HK
dc.identifier.authorityCheung, KMC=rp00387en_HK
dc.identifier.hkuros155816en_HK

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