title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
abstract: 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.
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Kieran J
authors: KJ
authors: Bunn
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Phil
authors: P
authors: Daniel
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Heleen S
authors: HS
authors: Rösken
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Adam C
authors: AC
authors: O'Neill
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Sophia R
authors: SR
authors: Cameron-Christie
authors: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: Tim
authors: T
authors: Morgan
authors: 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.
authors: Han G
authors: HG
authors: Brunner
authors: Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.
authors: Angeline
authors: A
authors: Lai
authors: Department of Otorhinolaryngology and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
authors: Henricus P M
authors: HP
authors: Kunst
authors: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors: David M
authors: DM
authors: Markie
authors: 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.
authors: Stephen P
authors: SP
authors: Robertson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology*; D000072261:Dishevelled Proteins; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology*; D016368:Frameshift Mutation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology*; D010026:Osteosclerosis / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D014564:Urogenital Abnormalities / Q000235:genetics* / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D049452:Green Fluorescent Proteins