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dc.contributor.authorMorrison, Nigel A
dc.contributor.authorStephens, Alexandre A
dc.contributor.authorOsato, Motomi
dc.contributor.authorPolly, Patsie
dc.contributor.authorTan, Timothy C
dc.contributor.authorYamashita, Namiko
dc.contributor.authorDoecke, James D
dc.contributor.authorPasco, Julie
dc.contributor.authorFozzard, Nicolette
dc.contributor.authorJones, Graeme
dc.contributor.authorRalston, Stuart H
dc.contributor.authorSambrook, Philip N
dc.contributor.authorPrince, Richard L
dc.contributor.authorNicholson, Geoff C
dc.date.accessioned2017-05-03T11:03:08Z
dc.date.available2017-05-03T11:03:08Z
dc.date.issued2012
dc.identifier.issn1932-6203
dc.identifier.doi10.1371/journal.pone.0042617
dc.identifier.urihttp://hdl.handle.net/10072/49125
dc.description.abstractRUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p=0.005). Femoral neck BMD was measured in all subjects (-0.6SD, p=0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent448122 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.language.isoen_US
dc.publisherPublic Library of Science
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrome42617-1
dc.relation.ispartofpagetoe42617-11
dc.relation.ispartofissue8
dc.relation.ispartofjournalPloS One
dc.relation.ispartofvolume7
dc.rights.retentionY
dc.subject.fieldofresearchQuantitative Genetics (incl. Disease and Trait Mapping Genetics)
dc.subject.fieldofresearchcode060412
dc.titleGlutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://www.plos.org/journals/license.html
gro.facultyGriffith Health, School of Medical Science
gro.rights.copyright© 2012 Morrison et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License CCAL. (http://www.plos.org/journals/license.html)
gro.date.issued2015-01-11T22:39:18Z
gro.hasfulltextFull Text
gro.griffith.authorMorrison, Nigel A.
gro.griffith.authorDoecke, James D.
gro.griffith.authorStephens, Alexandre
gro.griffith.authorFozzard, Nikki


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