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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
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TitleCOL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid
 
AuthorsHo, MSP3
Tsang, KY3
Lo, RLK3
Susic, M5
Mäkitie, O5 1
Chan, TWY3
Ng, VCW3
Sillence, DO6
BootHandford, RP2
Gibson, G4
Cheung, KMC3
Cole, WG5
Cheah, KSE3
Chan, D3
 
Issue Date2007
 
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
CitationHuman Molecular Genetics, 2007, v. 16 n. 10, p. 1201-1215 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddm067
 
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.
 
ISSN0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
DOIhttp://dx.doi.org/10.1093/hmg/ddm067
 
ISI Accession Number IDWOS:000247531100007
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorHo, MSP
 
dc.contributor.authorTsang, KY
 
dc.contributor.authorLo, RLK
 
dc.contributor.authorSusic, M
 
dc.contributor.authorMäkitie, O
 
dc.contributor.authorChan, TWY
 
dc.contributor.authorNg, VCW
 
dc.contributor.authorSillence, DO
 
dc.contributor.authorBootHandford, RP
 
dc.contributor.authorGibson, G
 
dc.contributor.authorCheung, KMC
 
dc.contributor.authorCole, WG
 
dc.contributor.authorCheah, KSE
 
dc.contributor.authorChan, D
 
dc.date.accessioned2010-09-06T06:02:35Z
 
dc.date.available2010-09-06T06:02:35Z
 
dc.date.issued2007
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationHuman Molecular Genetics, 2007, v. 16 n. 10, p. 1201-1215 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddm067
 
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddm067
 
dc.identifier.eissn1460-2083
 
dc.identifier.epage1215
 
dc.identifier.hkuros128587
 
dc.identifier.hkuros141285
 
dc.identifier.hkuros145974
 
dc.identifier.isiWOS:000247531100007
 
dc.identifier.issn0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
dc.identifier.issue10
 
dc.identifier.openurl
 
dc.identifier.pmid17403716
 
dc.identifier.scopuseid_2-s2.0-34447294827
 
dc.identifier.spage1201
 
dc.identifier.urihttp://hdl.handle.net/10722/68228
 
dc.identifier.volume16
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofHuman Molecular Genetics
 
dc.relation.referencesReferences in Scopus
 
dc.rightsHuman Molecular Genetics. Copyright © Oxford University Press.
 
dc.subject.meshAdolescent
 
dc.subject.meshAmino Acid Sequence
 
dc.subject.meshAnimals
 
dc.subject.meshBase Sequence
 
dc.subject.meshChondrocytes - metabolism
 
dc.subject.meshCodon, Nonsense
 
dc.subject.meshCollagen Type X - biosynthesis - genetics
 
dc.subject.meshDNA - genetics
 
dc.subject.meshFrameshift Mutation
 
dc.subject.meshGrowth Plate - pathology
 
dc.subject.meshHumans
 
dc.subject.meshMale
 
dc.subject.meshMice
 
dc.subject.meshMice, Mutant Strains
 
dc.subject.meshMice, Transgenic
 
dc.subject.meshOsteochondrodysplasias - genetics - metabolism - pathology
 
dc.subject.meshPhenotype
 
dc.subject.meshRNA, Messenger - genetics
 
dc.subject.meshSequence Deletion
 
dc.titleCOL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid
 
dc.typeArticle
 
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<description.abstract>Missense, 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 &#215; chains, which are truncated, were misfolded, unable to assemble into trimers and interfered with the assembly of normal &#945;1(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 &#945;1(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. &#169; 2007 Published by Oxford University Press.</description.abstract>
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Author Affiliations
  1. Helsingin Yliopisto
  2. University of Manchester
  3. The University of Hong Kong
  4. Henry Ford Hospital
  5. Hospital for Sick Children University of Toronto
  6. Children's Hospital At Westmead