Your browser doesn't support javascript.
loading
Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
Bunn, Kieran J; Daniel, Phil; Rösken, Heleen S; O'Neill, Adam C; Cameron-Christie, Sophia R; Morgan, Tim; Brunner, Han G; Lai, Angeline; Kunst, Henricus P M; Markie, David M; Robertson, Stephen P.
Afiliación
  • Bunn KJ; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Daniel P; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Rösken HS; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • O'Neill AC; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Cameron-Christie SR; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Morgan T; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Brunner HG; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands.
  • Lai A; Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.
  • Kunst HP; Department of Otorhinolaryngology and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
  • Markie DM; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • Robertson SP; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand. Electronic address: stephen.robertson@otago.ac.nz.
Am J Hum Genet ; 96(4): 623-30, 2015 Apr 02.
Article en En | MEDLINE | ID: mdl-25817014
Robinow syndrome (RS) is a phenotypically and genetically heterogeneous condition that can be caused by mutations in genes encoding components of the non-canonical Wnt signaling pathway. In contrast, germline mutations that act to increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes. Here, we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals. The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic sequence. We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation. In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic phenotype, revealed that the mutant allele was less active than the wild-type allele in the canonical Wnt signaling pathway. However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone. This work establishes that DVL1 mutations cause a specific RS subtype, RS-OS, and that the osteosclerosis associated with this subtype might be the result of an interaction between the wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Fosfoproteínas / Anomalías Urogenitales / Mutación del Sistema de Lectura / Deformidades Congénitas de las Extremidades / Anomalías Craneofaciales / Proteínas Adaptadoras Transductoras de Señales / Enanismo / Vía de Señalización Wnt Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2015 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Fosfoproteínas / Anomalías Urogenitales / Mutación del Sistema de Lectura / Deformidades Congénitas de las Extremidades / Anomalías Craneofaciales / Proteínas Adaptadoras Transductoras de Señales / Enanismo / Vía de Señalización Wnt Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2015 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos