Glutamine repeat mutations define a new RUNX2 related syndrome with decreased femoral neck BMD, decreased calcaneal ultrasound and increased risk of osteoporotic fracture

Stephens, A., Doecke, J., Ralston, S. H., Nicholson, G. C. and Morrison, N. A. (2005). Glutamine repeat mutations define a new RUNX2 related syndrome with decreased femoral neck BMD, decreased calcaneal ultrasound and increased risk of osteoporotic fracture. In: 27th Annual Meeting of the American Society for Bone and Mineral Research, Nashville, TN, United States, (S16-S16). 23-27 September 2005. doi:10.1002/jbmr.5650201302


Author Stephens, A.
Doecke, J.
Ralston, S. H.
Nicholson, G. C.
Morrison, N. A.
Title of paper Glutamine repeat mutations define a new RUNX2 related syndrome with decreased femoral neck BMD, decreased calcaneal ultrasound and increased risk of osteoporotic fracture
Conference name 27th Annual Meeting of the American Society for Bone and Mineral Research
Conference location Nashville, TN, United States
Conference dates 23-27 September 2005
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
Place of Publication Malden, MA, United States
Publisher Wiley-Blackwell
Publication Year 2005
Sub-type Published abstract
DOI 10.1002/jbmr.5650201302
ISSN 0884-0431
1523-4681
Volume 20
Issue S1
Start page S16
End page S16
Total pages 1
Language eng
Abstract/Summary RUNX2 is an essential transcription factor required for osteoblast differentiation and cartilage formation. Haplo-insufficiency of RUNX2 leads to cleidocranial dysplasia (CCD)a skeletal disorder characterized by gross skeletal dysgenesis. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Such repeat sequences are subject to high mutation rates through strand slippage during replication. Since none of the known mutations causing CCD map in the glutamine repeat region, we hypothesised that Q-repeat mutations would exist at high frequency and may be related to a more subtle bone phenotype than the morphological abnormalities of CCD. We screened 3600 subjects derived from three normal populations for Q-repeat mutations. A total of 28 subjects were identified who were heterozygous for a wild type allele and were carriers of Q variants: (deletions 15Q, 16Q, 17Q, and extensions 30Q). 12 of the 28 Q variant carriers had osteoporotic fracture. BMD data were available for each of the populations and were expressed in the form of Z-scores around the appropriate age-adjusted mean. Collectively, Q-repeat variants presented with significantly decreased femoral neck BMD (p=0.0006) with an effect of -0.56SD in BMD attributable to a single copy of the Q-variant in the presence of a wild type allele. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured in the calcaneus were available on 18 Q-variant subjects. Q-variants displayed significantly decreased BUA (p=0.006) with an effect of -0.65SD. To understand the mechanism via which the Q-repeat deletions and expansions were conferring decreased BMD and BUA, the transactivation function of the 16Q and 30Q alleles were analyzed using a RUNX2 reporter gene assay. 16Q and 30Q alleles were capable of transactivating target reporter plasmids but at levels significantly lower compared to wild type (23Q). Our analysis has identified a new class of functionally relevant RUNX2 variants in the Q repeat that influence BMD and fracture. Q-variants occur at the relatively high frequency ~0.8%, meaning that more than 2 million people in the US may be affected.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Conference Paper
Collection: School of Medicine Publications
 
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