Mutations in WNT1 cause different forms of bone fragility.
Am J Hum Genet
; 92(4): 565-74, 2013 Apr 04.
Article
en En
| MEDLINE
| ID: mdl-23499309
ABSTRACT
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 ß-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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Osteogénesis Imperfecta
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Osteoporosis
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Huesos
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Densidad Ósea
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Proteína Wnt1
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Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Child
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Child, preschool
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Female
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Humans
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Male
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Newborn
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Pregnancy
Idioma:
En
Revista:
Am J Hum Genet
Año:
2013
Tipo del documento:
Article
País de afiliación:
Alemania