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Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
Am J Hum Genet. 2015 Apr 02; 96(4):623-30.AJ

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+Show Affiliations

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.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.Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.Department of Otorhinolaryngology and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25817014

Citation

Bunn, Kieran J., et al. "Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome." American Journal of Human Genetics, vol. 96, no. 4, 2015, pp. 623-30.
Bunn KJ, Daniel P, Rösken HS, et al. Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. Am J Hum Genet. 2015;96(4):623-30.
Bunn, K. J., Daniel, P., Rösken, H. S., O'Neill, A. C., Cameron-Christie, S. R., Morgan, T., Brunner, H. G., Lai, A., Kunst, H. P., Markie, D. M., & Robertson, S. P. (2015). Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. American Journal of Human Genetics, 96(4), 623-30. https://doi.org/10.1016/j.ajhg.2015.02.010
Bunn KJ, et al. Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome. Am J Hum Genet. 2015 Apr 2;96(4):623-30. PubMed PMID: 25817014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. AU - Bunn,Kieran J, AU - Daniel,Phil, AU - Rösken,Heleen S, AU - O'Neill,Adam C, AU - Cameron-Christie,Sophia R, AU - Morgan,Tim, AU - Brunner,Han G, AU - Lai,Angeline, AU - Kunst,Henricus P M, AU - Markie,David M, AU - Robertson,Stephen P, Y1 - 2015/03/26/ PY - 2014/12/22/received PY - 2015/02/13/accepted PY - 2015/3/31/entrez PY - 2015/3/31/pubmed PY - 2015/5/30/medline SP - 623 EP - 30 JF - American journal of human genetics JO - Am J Hum Genet VL - 96 IS - 4 N2 - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/25817014/Mutations_in_DVL1_cause_an_osteosclerotic_form_of_Robinow_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(15)00063-4 DB - PRIME DP - Unbound Medicine ER -