Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation.
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.
School of Medical Sciences, Griffith University, Southport, Australia. N.Morrison@mailbox.gu.edu.au
Nigel A
NA
Morrison
Alexandre A
AA
Stephens
Motomi
M
Osato
Patsie
P
Polly
Timothy C
TC
Tan
Namiko
N
Yamashita
James D
JD
Doecke
Julie
J
Pasco
Nicolette
N
Fozzard
Graeme
G
Jones
Stuart H
SH
Ralston
Philip N
PN
Sambrook
Richard L
RL
Prince
Geoff C
GC
Nicholson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D002973:Cleidocranial Dysplasia / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005265:Femoral Neck Fractures / Q000235:genetics / Q000503:physiopathology; D005272:Femur Neck / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005973:Glutamine; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009010:Monte Carlo Method; D009154:Mutation; D041681:NIH 3T3 Cells; D018167:Receptors, Calcitriol / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D015533:Transcriptional Activation / Q000235:genetics*; D014463:Ultrasonography
D050659:Core Binding Factor Alpha 1 Subunit; D018167:Receptors, Calcitriol; D005973:Glutamine