posted on 2023-05-17, 15:13authored byMorrison, NA, Stephens, AA, Osato, M, Polly, P, Tan, TC, Yamashita, N, Doecke, JD, Pasco, J, Fozzard, N, Graeme JonesGraeme Jones, Ralston, SH, Sambrook, PN, Prince, RL, Nicholson, GC
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.
History
Publication title
PLoS One
Volume
7
Issue
8
Article number
e42617
Number
e42617
Pagination
1-11
ISSN
1932-6203
Department/School
Menzies Institute for Medical Research
Publisher
Public Library of Science
Place of publication
United States
Rights statement
Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0) http://creativecommons.org/licenses/by/3.0/