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Article: COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid

TitleCOL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid
Authors
Issue Date2007
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2007, v. 16 n. 10, p. 1201-1215 How to Cite?
AbstractMissense, nonsense and frame-shift mutations in the collagen X gene (COL10A1) result in metaphyseal chondrodysplasia type Schmid (MCDS). Complete degradation of mutant COL10A1 mRNA by nonsense-mediated decay in human MCDS cartilage implicates haploinsufficiency in the pathogenesis for nonsense mutations in vivo. However, the mechanism is unclear in situations where the mutant mRNA persist. We show that nonsense/frame-shift mutations can elicit a gain-of-function effect, affecting chondrocyte differentiation in the growth plate. In an MCDS proband, heterozygous for a p.Y663X nonsense mutation, the growth plate cartilage contained 64% wild-type and 36% mutant mRNA and the hypertrophic zone was disorganized and expanded. The in vitro translated mutant collagen × chains, which are truncated, were misfolded, unable to assemble into trimers and interfered with the assembly of normal α1(X) chains into trimers. Unlike Col10a1 null mutants, transgenic mice (FCdel) bearing the mouse equivalent of a human MCDS p.P620fsX621 mutation, displayed typical characteristics of MCDS with disproportionate shortening of limbs and early onset coxa vara. In FCdel mice, the degree of expansion of the hypertrophic zones was transgene-dosage dependent, being most severe in mice homozygous for the transgene. Chondrocytes in the lower region of the expanded hypertrophic zone expressed markers uncharacteristic of hypertrophic chondrocytes, indicating that differentiation was disrupted. Misfolded FCdel α1(X) chains were retained within the endoplasmic reticulum of hypertrophic chondrocytes, activating the unfolded protein response. Our findings provide strong in vivo evidence for a gain-of-function effect that is linked to the activation of endoplasmic reticulum-stress response and altered chondrocyte differentiation, as a possible molecular pathogenesis for MCDS. © 2007 Published by Oxford University Press.
Persistent Identifierhttp://hdl.handle.net/10722/68228
ISSN
2015 Impact Factor: 5.985
2015 SCImago Journal Rankings: 4.288
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHo, MSPen_HK
dc.contributor.authorTsang, KYen_HK
dc.contributor.authorLo, RLKen_HK
dc.contributor.authorSusic, Men_HK
dc.contributor.authorMäkitie, Oen_HK
dc.contributor.authorChan, TWYen_HK
dc.contributor.authorNg, VCWen_HK
dc.contributor.authorSillence, DOen_HK
dc.contributor.authorBootHandford, RPen_HK
dc.contributor.authorGibson, Gen_HK
dc.contributor.authorCheung, KMCen_HK
dc.contributor.authorCole, WGen_HK
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorChan, Den_HK
dc.date.accessioned2010-09-06T06:02:35Z-
dc.date.available2010-09-06T06:02:35Z-
dc.date.issued2007en_HK
dc.identifier.citationHuman Molecular Genetics, 2007, v. 16 n. 10, p. 1201-1215en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68228-
dc.description.abstractMissense, nonsense and frame-shift mutations in the collagen X gene (COL10A1) result in metaphyseal chondrodysplasia type Schmid (MCDS). Complete degradation of mutant COL10A1 mRNA by nonsense-mediated decay in human MCDS cartilage implicates haploinsufficiency in the pathogenesis for nonsense mutations in vivo. However, the mechanism is unclear in situations where the mutant mRNA persist. We show that nonsense/frame-shift mutations can elicit a gain-of-function effect, affecting chondrocyte differentiation in the growth plate. In an MCDS proband, heterozygous for a p.Y663X nonsense mutation, the growth plate cartilage contained 64% wild-type and 36% mutant mRNA and the hypertrophic zone was disorganized and expanded. The in vitro translated mutant collagen × chains, which are truncated, were misfolded, unable to assemble into trimers and interfered with the assembly of normal α1(X) chains into trimers. Unlike Col10a1 null mutants, transgenic mice (FCdel) bearing the mouse equivalent of a human MCDS p.P620fsX621 mutation, displayed typical characteristics of MCDS with disproportionate shortening of limbs and early onset coxa vara. In FCdel mice, the degree of expansion of the hypertrophic zones was transgene-dosage dependent, being most severe in mice homozygous for the transgene. Chondrocytes in the lower region of the expanded hypertrophic zone expressed markers uncharacteristic of hypertrophic chondrocytes, indicating that differentiation was disrupted. Misfolded FCdel α1(X) chains were retained within the endoplasmic reticulum of hypertrophic chondrocytes, activating the unfolded protein response. Our findings provide strong in vivo evidence for a gain-of-function effect that is linked to the activation of endoplasmic reticulum-stress response and altered chondrocyte differentiation, as a possible molecular pathogenesis for MCDS. © 2007 Published by Oxford University Press.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.rightsHuman Molecular Genetics. Copyright © Oxford University Press.en_HK
dc.subject.meshAdolescenten_HK
dc.subject.meshAmino Acid Sequenceen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshChondrocytes - metabolismen_HK
dc.subject.meshCodon, Nonsenseen_HK
dc.subject.meshCollagen Type X - biosynthesis - geneticsen_HK
dc.subject.meshDNA - geneticsen_HK
dc.subject.meshFrameshift Mutationen_HK
dc.subject.meshGrowth Plate - pathologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Mutant Strainsen_HK
dc.subject.meshMice, Transgenicen_HK
dc.subject.meshOsteochondrodysplasias - genetics - metabolism - pathologyen_HK
dc.subject.meshPhenotypeen_HK
dc.subject.meshRNA, Messenger - geneticsen_HK
dc.subject.meshSequence Deletionen_HK
dc.titleCOL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmiden_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=16&issue=10&spage=1201&epage=15&date=2007&atitle=COL10A1+nonsense+and+frame-shift+mutations+have+a+gain-of-function+effect+on+the+growth+plate+in+human+and+mouse+metaphyseal+chondrodysplasia+type+Schmid.en_HK
dc.identifier.emailCheung, KMC:cheungmc@hku.hken_HK
dc.identifier.emailCheah, KSE:hrmbdkc@hku.hken_HK
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.authorityCheung, KMC=rp00387en_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/hmg/ddm067en_HK
dc.identifier.pmid17403716-
dc.identifier.scopuseid_2-s2.0-34447294827en_HK
dc.identifier.hkuros128587en_HK
dc.identifier.hkuros141285-
dc.identifier.hkuros145974-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34447294827&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1201en_HK
dc.identifier.epage1215en_HK
dc.identifier.eissn1460-2083-
dc.identifier.isiWOS:000247531100007-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridHo, MSP=7403080540en_HK
dc.identifier.scopusauthoridTsang, KY=22635904200en_HK
dc.identifier.scopusauthoridLo, RLK=35080754300en_HK
dc.identifier.scopusauthoridSusic, M=7006327601en_HK
dc.identifier.scopusauthoridMäkitie, O=7003423534en_HK
dc.identifier.scopusauthoridChan, TWY=34967926200en_HK
dc.identifier.scopusauthoridNg, VCW=8215749500en_HK
dc.identifier.scopusauthoridSillence, DO=7006527427en_HK
dc.identifier.scopusauthoridBootHandford, RP=7004054302en_HK
dc.identifier.scopusauthoridGibson, G=7402074438en_HK
dc.identifier.scopusauthoridCheung, KMC=7402406754en_HK
dc.identifier.scopusauthoridCole, WG=7201518727en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK

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