| First Author | Keupp K | Year | 2013 |
| Journal | Am J Hum Genet | Volume | 92 |
| Issue | 4 | Pages | 565-74 |
| PubMed ID | 23499309 | Mgi Jnum | J:203641 |
| Mgi Id | MGI:5528420 | Doi | 10.1016/j.ajhg.2013.02.010 |
| Citation | Keupp K, et al. (2013) Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92(4):565-74 |
| abstractText | We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis. |
