Tags

Type your tag names separated by a space and hit enter

Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome.
J Dent Res. 2017 Oct; 96(11):1265-1272.JD

Abstract

The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses-wt WNT5A, WNT5AC83S, or WNT5AC182R-all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein.

Authors+Show Affiliations

1 Life Sciences Institute, Department of Oral Health Sciences, University of British Columbia, Vancouver, BC, Canada.1 Life Sciences Institute, Department of Oral Health Sciences, University of British Columbia, Vancouver, BC, Canada.1 Life Sciences Institute, Department of Oral Health Sciences, University of British Columbia, Vancouver, BC, Canada.1 Life Sciences Institute, Department of Oral Health Sciences, University of British Columbia, Vancouver, BC, Canada.1 Life Sciences Institute, Department of Oral Health Sciences, University of British Columbia, Vancouver, BC, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28662348

Citation

Hosseini-Farahabadi, S, et al. "Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome." Journal of Dental Research, vol. 96, no. 11, 2017, pp. 1265-1272.
Hosseini-Farahabadi S, Gignac SJ, Danescu A, et al. Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. J Dent Res. 2017;96(11):1265-1272.
Hosseini-Farahabadi, S., Gignac, S. J., Danescu, A., Fu, K., & Richman, J. M. (2017). Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. Journal of Dental Research, 96(11), 1265-1272. https://doi.org/10.1177/0022034517716916
Hosseini-Farahabadi S, et al. Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. J Dent Res. 2017;96(11):1265-1272. PubMed PMID: 28662348.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. AU - Hosseini-Farahabadi,S, AU - Gignac,S J, AU - Danescu,A, AU - Fu,K, AU - Richman,J M, Y1 - 2017/06/29/ PY - 2017/7/1/pubmed PY - 2017/10/3/medline PY - 2017/6/30/entrez KW - cell polarity KW - chick embryo KW - chondrocytes KW - embryonic development KW - face KW - rare diseases SP - 1265 EP - 1272 JF - Journal of dental research JO - J Dent Res VL - 96 IS - 11 N2 - The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses-wt WNT5A, WNT5AC83S, or WNT5AC182R-all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein. SN - 1544-0591 UR - https://www.unboundmedicine.com/medline/citation/28662348/Abnormal_WNT5A_Signaling_Causes_Mandibular_Hypoplasia_in_Robinow_Syndrome_ L2 - https://journals.sagepub.com/doi/10.1177/0022034517716916?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -