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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.
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TitleA splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas.
 
AuthorsYang, L1
Hui, WS
Chan, WC
Ng, VC
Yam, TH
Leung, HC
Huang, JD
Shum, DK
Jie, Q
Cheung, KM
Cheah, KS
Luo, Z
Chan, D
 
Issue Date2010
 
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.elsevier.com/locate/orthres
 
CitationJournal Of Orthopaedic Research : Official Publication Of The Orthopaedic Research Society, 2010, v. 28 n. 11, p. 1522-1530 [How to Cite?]
DOI: http://dx.doi.org/10.1002/jor.21162
 
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.
 
ISSN1554-527X
 
DOIhttp://dx.doi.org/10.1002/jor.21162
 
ISI Accession Number IDWOS:000282917900019
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).

 
GrantsDevelopmental genomics and skeletal research
 
DC FieldValue
dc.contributor.authorYang, L
 
dc.contributor.authorHui, WS
 
dc.contributor.authorChan, WC
 
dc.contributor.authorNg, VC
 
dc.contributor.authorYam, TH
 
dc.contributor.authorLeung, HC
 
dc.contributor.authorHuang, JD
 
dc.contributor.authorShum, DK
 
dc.contributor.authorJie, Q
 
dc.contributor.authorCheung, KM
 
dc.contributor.authorCheah, KS
 
dc.contributor.authorLuo, Z
 
dc.contributor.authorChan, D
 
dc.date.accessioned2011-09-23T05:43:00Z
 
dc.date.available2011-09-23T05:43:00Z
 
dc.date.issued2010
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Orthopaedic Research : Official Publication Of The Orthopaedic Research Society, 2010, v. 28 n. 11, p. 1522-1530 [How to Cite?]
DOI: http://dx.doi.org/10.1002/jor.21162
 
dc.identifier.doihttp://dx.doi.org/10.1002/jor.21162
 
dc.identifier.eissn1554-527X
 
dc.identifier.epage1530
 
dc.identifier.hkuros184372
 
dc.identifier.isiWOS:000282917900019
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).

 
dc.identifier.issn1554-527X
 
dc.identifier.issue11
 
dc.identifier.pmid20872591
 
dc.identifier.scopuseid_2-s2.0-77957994385
 
dc.identifier.spage1522
 
dc.identifier.urihttp://hdl.handle.net/10722/138950
 
dc.identifier.volume28
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.elsevier.com/locate/orthres
 
dc.relation.ispartofJournal of orthopaedic research : official publication of the Orthopaedic Research Society
 
dc.relation.projectDevelopmental genomics and skeletal research
 
dc.rightsJournal of Orthopaedic Research. Copyright © John Wiley & Sons, Inc.
 
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.
 
dc.typeArticle
 
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<contributor.author>Hui, WS</contributor.author>
<contributor.author>Chan, WC</contributor.author>
<contributor.author>Ng, VC</contributor.author>
<contributor.author>Yam, TH</contributor.author>
<contributor.author>Leung, HC</contributor.author>
<contributor.author>Huang, JD</contributor.author>
<contributor.author>Shum, DK</contributor.author>
<contributor.author>Jie, Q</contributor.author>
<contributor.author>Cheung, KM</contributor.author>
<contributor.author>Cheah, KS</contributor.author>
<contributor.author>Luo, Z</contributor.author>
<contributor.author>Chan, D</contributor.author>
<date.accessioned>2011-09-23T05:43:00Z</date.accessioned>
<date.available>2011-09-23T05:43:00Z</date.available>
<date.issued>2010</date.issued>
<identifier.citation>Journal Of Orthopaedic Research : Official Publication Of The Orthopaedic Research Society, 2010, v. 28 n. 11, p. 1522-1530</identifier.citation>
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<description.abstract>Multiple 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 &gt; 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. &#169; 2010 Orthopaedic Research Society.</description.abstract>
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<subject.mesh>Exostoses, Multiple Hereditary - genetics</subject.mesh>
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Author Affiliations
  1. The University of Hong Kong