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Title: Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation
Authors: Morrison N.A.
Stephens A.A.
Osato M. 
Polly P.
Tan T.C.
Yamashita N.
Doecke J.D.
Pasco J.
Fozzard N.
Jones G.
Ralston S.H.
Sambrook P.N.
Prince R.L.
Nicholson G.C.
Keywords: polyglutamine
transcription factor RUNX2
vitamin D receptor
bone densitometry
bone density
femur neck
gene frequency
gene function
gene mutation
gene targeting
genetic association
genetic variability
mutational analysis
mutator gene
Runx2 gene
Aged, 80 and over
Bone Density
Cleidocranial Dysplasia
Core Binding Factor Alpha 1 Subunit
Femoral Neck Fractures
Femur Neck
Genetic Predisposition to Disease
HEK293 Cells
Monte Carlo Method
NIH 3T3 Cells
Receptors, Calcitriol
Repetitive Sequences, Amino Acid
Transcriptional Activation
Issue Date: 2012
Publisher: Public Library of Science
Citation: Morrison N.A., Stephens A.A., Osato M., Polly P., Tan T.C., Yamashita N., Doecke J.D., Pasco J., Fozzard N., Jones G., Ralston S.H., Sambrook P.N., Prince R.L., Nicholson G.C. (2012). Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation. PLoS ONE 7 (8) : e42617. ScholarBank@NUS Repository.
Abstract: 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. © 2012 Morrison et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0042617
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