Rare variations in WNT3A and DKK1 may predispose carriers to primary osteoporosis.
Childhood-onset primary osteoporosis is manifested as reduced bone mineral density, peripheral fractures and/or vertebral compression fractures. Until now, only mutations in LRP5 have been shown to cause the disorder. Candidate gene analyses were performed on 15 patients with primary osteoporosis and 80 healthy controls using CSGE and sequencing. The genes studied included DKK1, DKK2, WNT3A, WNT10B, AXIN1, SOST, TPH1 and 5-HTR1B. Two rare variants in WNT3A (c.152A > G, p.K51R) and DKK1 (c.359G > T, p.R120L) were identified in two patients and their affected family members, but not in control subjects, suggesting a significance for the skeletal phenotype. The in vitro studies of variants showed reduced signaling activity in p.K51R-Wnt3a, while no differences were observed between the WT and variant forms of DKK1. This study addresses the role of other components of the canonical Wnt signaling pathway besides LRP5 in primary osteoporosis, and putatively associates WNT3A and DKK1 variants with the disorder. Future functional studies are needed to elucidate the functional effects of the variants.
Oulu Center for Cell-Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, PO Box 5000, 90014 University of Oulu, Finland. johanna.korvala@oulu.fi
Johanna
J
Korvala
Marika
M
Löija
Outi
O
Mäkitie
Etienne
E
Sochett
Harald
H
Jüppner
Dirk
D
Schnabel
Stefano
S
Mora
William G
WG
Cole
Leena
L
Ala-Kokko
Minna
M
Männikkö
D000293:Adolescent; D000818:Animals; D016466:CHO Cells; D016022:Case-Control Studies; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D010024:Osteoporosis / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein