Abstract for presentation at 11th International Congress of Human Genetics

Variation in RUNX2 related to bone density and fracture

  • Nigel Morrison, Griffith University, Australia
  • Mr Alex Stephens, Griffith University, Australia
  • Mr James Doecke, Griffith University, Australia
  • Dr Stuart Ralston, Rheumatic Diseases Unit, Western General Hospital, Edinburgh EH4 2XU, UK., United Kingdom
  • Dr Richard Prince, University of Western Australia, Australia
  • Dr Geoff Nicholson, Australia

    • The RUNX2 transcription factor is responsible for differentiation of osteoblasts from mesenchymal precursor cells. A notable feature of the RUNX2 protein is a glutamine and alanine repeat sequence (23Q/17A repeat). Mutations in RUNX2 have been associated with cleidocranial dysplasia (CCD), a condition in which haploinsufficiency leads to loss of skeletal elements mostly derived from intramembranous bone development. As mutations in the Q-repeat are not associated with CCD, we hypothesized that glutamine repeat variants may influence adult bone mineral density (BMD). DNA samples from epidemiological studies of bone density were obtained from normal human volunteers in studies of the epidemiology of bone loss. BMD was measured using dual energy absorptiometry (DEXA) and ultrasound. BMD data were expressed as Z-scores around the appropriate age-mean. Of 3600 subjects tested for Q variation, 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). All Q variants had a normal alanine repeat (17 amino acids) and all were heterozygous with a normal 23Q/17A allele. One individual was observed with an extended alanine repeat. Q-repeat variants presented with significantly decreased femoral neck BMD (p=0.0006) with a reduction of 0.56SD. Q-variants had significantly decreased ultrasound measures (p=0.006) with an effect of similar magnitude (0.65SD decrease). The transactivation function of the 16Q and 30Q alleles were analyzed using a RUNX2 reporter gene assay. 16Q and 30Q alleles displayed transactivation function but at levels significantly lower compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency ~0.8%. These mutations significantly alter BMD and display impaired transactivation function introducing a new class of functionally relevant RUNX2 mutants.

    Conference Organiser - ICMS Pty Ltd