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Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation

Morrison, Nigel A., Stephens, Alexandre A., Osato, Motomi, Polly, Patsie, Tan, Timothy C., Yamashita, Namiko, Doecke, James D., Pasco, Julie, Fozzard, Nicolette, Jones, Graeme, Ralston, Stuart H., Sambrook, Philip N., Prince, Richard L. and Nicholson, Geoff C. 2012, Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation, PLoS One, vol. 7, no. 8, Article number e42617, pp. 1-11, doi: 10.1371/journal.pone.0042617.

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Title Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation
Author(s) Morrison, Nigel A.
Stephens, Alexandre A.
Osato, Motomi
Polly, Patsie
Tan, Timothy C.
Yamashita, Namiko
Doecke, James D.
Pasco, JulieORCID iD for Pasco, Julie orcid.org/0000-0002-8968-4714
Fozzard, Nicolette
Jones, Graeme
Ralston, Stuart H.
Sambrook, Philip N.
Prince, Richard L.
Nicholson, Geoff C.
Journal name PLoS One
Volume number 7
Issue number 8
Season Article number e42617
Start page 1
End page 11
Total pages 11
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2012-08-13
ISSN 1932-6203
Keyword(s) polyglutamine
transcription factor RUNX2
vitamin D receptor
Summary RUNX2 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.
Notes This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Language eng
DOI 10.1371/journal.pone.0042617
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2012, Morrison et al.
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30048702

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.