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, M6
Mäkitie, O1 6
Chan, TWY3
Ng, VCW3
Sillence, DO5
BootHandford, RP2
Gibson, G4
Cheung, KMC3
Cole, WG6
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
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
DOIhttp://dx.doi.org/10.1093/hmg/ddm067
ISI Accession Number IDWOS:000247531100007
ReferencesReferences in Scopus
DC Field
Value
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.epage1215
dc.identifier.hkuros128587
dc.identifier.hkuros141285
dc.identifier.hkuros145974
dc.identifier.isiWOS:000247531100007
dc.identifier.issn0964-6906
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
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
Author Affiliations
  1. Helsingin Yliopisto
  2. University of Manchester
  3. The University of Hong Kong
  4. Henry Ford Hospital
  5. Children's Hospital At Westmead
  6. Hospital for Sick Children, Toronto