Glutamine Repeat Variants in Human RUNX2 Associated with Decreased Femoral Neck BMD, Broadband Ultrasound Attenuation and Target Gene Transactivation

Nigel A Morrison, Alexandre A Stephens, Motomi Osato, Patsie Polly, Timothy C Tan, Namiko Yamashita, James D Doecke, Julie Pasco, Nicolette Fozzard, Graeme Jones, Stuart H Ralston, Philip N Sambrook, Richard L Prince and Geoff C Nicholson

PLOS ONE, 2012, vol. 7, issue 8, 1-11

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.

Date: 2012
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0042617

DOI: 10.1371/journal.pone.0042617

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