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Article: A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas.

TitleA splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas.
Authors
Issue Date2010
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.elsevier.com/locate/orthres
Citation
Journal Of Orthopaedic Research : Official Publication Of The Orthopaedic Research Society, 2010, v. 28 n. 11, p. 1522-1530 How to Cite?
AbstractMultiple osteochondromas (MO) is an autosomal-dominant disorder and mutations in EXT1 and EXT2 account up to 78% of the cases studied, including missense, nonsense, frameshift, and splice-site mutations. EXT1 and EXT2 encode glycosyltransferases required for the synthesis of heparan sulfate (HS) chains. The molecular pathogenesis underlying these mutations is still largely unknown. A heterozygous c.1173+ 1G > T (EXT2) mutation was identified in a three-generation 34-member MO family and is present in all 19 affected members. The consequence of this mutation is exon 7 being spliced out, and the result is a shift in the codon-reading frame from position 360 (R360) of the amino acid sequence leading to a premature termination codon, and the mutant mRNA is degraded to an undetectable level. Interestingly, HS glycosaminoglycans were also undetectable in the cartilage cap of the tumors by immunostaining. Full penetrance of this mutation in all affected members ranging from 5 to 70 years of age suggests this primary defect in EXT2 mRNA level, in conjunction with other cellular changes such as enhanced heparanase expression, can produce profound effect on the synthesis of HS chains in cartilage, the consequence of which impacts on the regulation of chondrocyte proliferation and differentiation. © 2010 Orthopaedic Research Society.
Persistent Identifierhttp://hdl.handle.net/10722/138950
ISSN
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants CouncilN_HKU011/00
University Grants Council of Hong KongAoE/M-04/04
National Natural Science Foundation of China3001161944
30300355
Funding Information:

This work was supported by grants from the Research Grants Council (N_HKU011/00), University Grants Council of Hong Kong (AoE/M-04/04), and National Natural Science Foundation of China (3001161944 and 30300355).

Grants

 

DC FieldValueLanguage
dc.contributor.authorYang, Len_HK
dc.contributor.authorHui, WSen_HK
dc.contributor.authorChan, WCen_HK
dc.contributor.authorNg, VCen_HK
dc.contributor.authorYam, THen_HK
dc.contributor.authorLeung, HCen_HK
dc.contributor.authorHuang, JDen_HK
dc.contributor.authorShum, DKen_HK
dc.contributor.authorJie, Qen_HK
dc.contributor.authorCheung, KMen_HK
dc.contributor.authorCheah, KSen_HK
dc.contributor.authorLuo, Zen_HK
dc.contributor.authorChan, Den_HK
dc.date.accessioned2011-09-23T05:43:00Z-
dc.date.available2011-09-23T05:43:00Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Orthopaedic Research : Official Publication Of The Orthopaedic Research Society, 2010, v. 28 n. 11, p. 1522-1530en_HK
dc.identifier.issn1554-527Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/138950-
dc.description.abstractMultiple osteochondromas (MO) is an autosomal-dominant disorder and mutations in EXT1 and EXT2 account up to 78% of the cases studied, including missense, nonsense, frameshift, and splice-site mutations. EXT1 and EXT2 encode glycosyltransferases required for the synthesis of heparan sulfate (HS) chains. The molecular pathogenesis underlying these mutations is still largely unknown. A heterozygous c.1173+ 1G > T (EXT2) mutation was identified in a three-generation 34-member MO family and is present in all 19 affected members. The consequence of this mutation is exon 7 being spliced out, and the result is a shift in the codon-reading frame from position 360 (R360) of the amino acid sequence leading to a premature termination codon, and the mutant mRNA is degraded to an undetectable level. Interestingly, HS glycosaminoglycans were also undetectable in the cartilage cap of the tumors by immunostaining. Full penetrance of this mutation in all affected members ranging from 5 to 70 years of age suggests this primary defect in EXT2 mRNA level, in conjunction with other cellular changes such as enhanced heparanase expression, can produce profound effect on the synthesis of HS chains in cartilage, the consequence of which impacts on the regulation of chondrocyte proliferation and differentiation. © 2010 Orthopaedic Research Society.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.elsevier.com/locate/orthresen_US
dc.relation.ispartofJournal of orthopaedic research : official publication of the Orthopaedic Research Societyen_HK
dc.rightsJournal of Orthopaedic Research. Copyright © John Wiley & Sons, Inc.en_US
dc.subject.meshExostoses, Multiple Hereditary - genetics-
dc.subject.meshGlucuronidase - genetics-
dc.subject.meshMutation-
dc.subject.meshN-Acetylglucosaminyltransferases - genetics-
dc.subject.meshRNA, Messenger - metabolism-
dc.titleA splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas.en_HK
dc.typeArticleen_HK
dc.identifier.emailHuang, JD:jdhuang@hkucc.hku.hken_HK
dc.identifier.emailShum, DK:shumdkhk@hkucc.hku.hken_HK
dc.identifier.emailCheung, KM:cheungmc@hku.hken_HK
dc.identifier.emailCheah, KS:hrmbdkc@hku.hken_HK
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.authorityHuang, JD=rp00451en_HK
dc.identifier.authorityShum, DK=rp00321en_HK
dc.identifier.authorityCheung, KM=rp00387en_HK
dc.identifier.authorityCheah, KS=rp00342en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/jor.21162en_HK
dc.identifier.pmid20872591-
dc.identifier.scopuseid_2-s2.0-77957994385en_HK
dc.identifier.hkuros184372en_US
dc.identifier.volume28en_HK
dc.identifier.issue11en_HK
dc.identifier.spage1522en_HK
dc.identifier.epage1530en_HK
dc.identifier.eissn1554-527X-
dc.identifier.isiWOS:000282917900019-
dc.relation.projectDevelopmental genomics and skeletal research-
dc.identifier.scopusauthoridYang, L=36609619900en_HK
dc.identifier.scopusauthoridHui, WS=7103196473en_HK
dc.identifier.scopusauthoridChan, WC=24545687600en_HK
dc.identifier.scopusauthoridNg, VC=8215749500en_HK
dc.identifier.scopusauthoridYam, TH=36609651100en_HK
dc.identifier.scopusauthoridLeung, HC=36608413100en_HK
dc.identifier.scopusauthoridHuang, JD=8108660600en_HK
dc.identifier.scopusauthoridShum, DK=7004824447en_HK
dc.identifier.scopusauthoridJie, Q=55216963400en_HK
dc.identifier.scopusauthoridCheung, KM=7402406754en_HK
dc.identifier.scopusauthoridCheah, KS=35387746200en_HK
dc.identifier.scopusauthoridLuo, Z=36608613700en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK

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