Three independent studies have shown that WNT1 mutations are responsible for bone fragility. WNT1 mutations were found in families with moderately severe recessive osteogenesis imperfecta and early-onset osteoporosis. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the co-receptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density.
Osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Mutated WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling.
These sudies identified novel molecular defects responsible for recessive OI and potential new therapeutic targets for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
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Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, Fernandez BA, Elsayed SM, Elsobky E, Verma I, Nair S, Turner EH, Smith JD, Jarvik GP, Byers PH. WNT1 Mutations in Families Affected by Moderately Severe and Progressive Recessive Osteogenesis Imperfecta. Am J Hum Genet. 2013 Apr 4;92(4):590-7
Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grünhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparrós-Martín JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schönau E, Ruiz-Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B.Mutations in WNT1 Cause Different Forms of Bone Fragility. Am J Hum Genet. 2013 Apr 4;92(4):565-74.
Posted by Nicola Brunetti-Pierri, MD, FACMG