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Conference Paper: Context dependent impact of the Y440X campomelic dysplasia Sox9 mutation

TitleContext dependent impact of the Y440X campomelic dysplasia Sox9 mutation
Authors
Issue Date2008
PublisherHong Kong Society of Medical Genetics
Citation
ACGA-HKSMG International Conference on Genetic and Genomic Medicine, Hong Kong, 8-11 June 2008 How to Cite?
AbstractMutations in the human, SOX9 gene are associated with the skeletal malformation syndrome, campomelic dysplasia (CD) and sex reversal. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a role for SOX9 in ear development. Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as extracellular matrix genes, Col2a1, Col9a1, Col11a2 and aggrecan. Because all the SOX9 mutations are heterozygous, are distributed throughout the gene and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficiency 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 in 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). We compared the phenotypic impact of the Sox9Y440X mutation with a Sox9 null mutation. These studies point to an essential role for Sox9 in inner ear and intervertebral disc development and context dependent mechanisms for the Y440X nonsense mutation. This work was supported by grants from the Hong Kong Research Grants Council and University Grants Council HKU7222/97M, HKU2/02C, HKU2/01C, HKU 4/05C, AoE/M-04/04
Persistent Identifierhttp://hdl.handle.net/10722/96729

 

DC FieldValueLanguage
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorSzeto, YYen_HK
dc.contributor.authorAu, YKen_HK
dc.contributor.authorWynn, Sen_HK
dc.contributor.authorGeng, Gen_HK
dc.contributor.authorChan, YSen_HK
dc.contributor.authorChan, WYen_HK
dc.contributor.authorCheung, KMCen_HK
dc.contributor.authorFritzsch, Ben_HK
dc.date.accessioned2010-09-25T16:42:52Z-
dc.date.available2010-09-25T16:42:52Z-
dc.date.issued2008en_HK
dc.identifier.citationACGA-HKSMG International Conference on Genetic and Genomic Medicine, Hong Kong, 8-11 June 2008-
dc.identifier.urihttp://hdl.handle.net/10722/96729-
dc.description.abstractMutations in the human, SOX9 gene are associated with the skeletal malformation syndrome, campomelic dysplasia (CD) and sex reversal. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a role for SOX9 in ear development. Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as extracellular matrix genes, Col2a1, Col9a1, Col11a2 and aggrecan. Because all the SOX9 mutations are heterozygous, are distributed throughout the gene and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficiency 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 in 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). We compared the phenotypic impact of the Sox9Y440X mutation with a Sox9 null mutation. These studies point to an essential role for Sox9 in inner ear and intervertebral disc development and context dependent mechanisms for the Y440X nonsense mutation. This work was supported by grants from the Hong Kong Research Grants Council and University Grants Council HKU7222/97M, HKU2/02C, HKU2/01C, HKU 4/05C, AoE/M-04/04-
dc.languageengen_HK
dc.publisherHong Kong Society of Medical Genetics-
dc.relation.ispartofACGA-HKSMG International Conferenceen_HK
dc.titleContext dependent impact of the Y440X campomelic dysplasia Sox9 mutationen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailCheah, KSE: hrmbdkc@hkusua.hku.hken_HK
dc.identifier.emailSzeto, YY: yukyeeszeto@yahoo.com.hken_HK
dc.identifier.emailAu, YK: h0294066@hkusua.hku.hken_HK
dc.identifier.emailChan, YS: yschan@hkucc.hku.hken_HK
dc.identifier.emailCheung, KMC: cheungmc@hku.hken_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityChan, YS=rp00318en_HK
dc.identifier.authorityCheung, KMC=rp00387en_HK
dc.identifier.hkuros144284en_HK

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