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Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
Hum Mol Genet. 2019 07 15; 28(14):2395-2414.HM

Abstract

Heterozygous missense mutations in several genes in the WNT5A signaling pathway cause autosomal dominant Robinow syndrome 1 (DRS1). Our objective was to clarify the functional impact of a missense mutation in WNT5A on the skeleton, one of the main affected tissues in RS. We delivered avian replication competent retroviruses (RCAS) containing human wild-type WNT5A (wtWNT5A), WNT5AC83S variant or GFP/AlkPO4 control genes to the chicken embryo limb. Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter and 200% wider than controls. In contrast, bone dimensions in wtWNT5A limbs were slightly affected (20% shorter, 25% wider) but ossification occurred on schedule. The dysmorphology of bones was established during cartilage differentiation. Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of disrupted planar cell polarity (PCP) mechanisms. Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability. Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted, compared to wtWNT5A. Thus, in the chicken and human, RS phenotypes are produced from the C83S mutation, even though the variant protein is less abundant than wtWNT5A. We conclude the variant protein has dominant-negative effects on chondrogenesis leading to limb abnormalities.

Authors+Show Affiliations

Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, Canada.

Pub Type(s)

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

Language

eng

PubMed ID

31032853

Citation

Gignac, Sarah J., et al. "Robinow Syndrome Skeletal Phenotypes Caused By the WNT5AC83S Variant Are Due to Dominant Interference With Chondrogenesis." Human Molecular Genetics, vol. 28, no. 14, 2019, pp. 2395-2414.
Gignac SJ, Hosseini-Farahabadi S, Akazawa T, et al. Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis. Hum Mol Genet. 2019;28(14):2395-2414.
Gignac, S. J., Hosseini-Farahabadi, S., Akazawa, T., Schuck, N. J., Fu, K., & Richman, J. M. (2019). Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis. Human Molecular Genetics, 28(14), 2395-2414. https://doi.org/10.1093/hmg/ddz071
Gignac SJ, et al. Robinow Syndrome Skeletal Phenotypes Caused By the WNT5AC83S Variant Are Due to Dominant Interference With Chondrogenesis. Hum Mol Genet. 2019 07 15;28(14):2395-2414. PubMed PMID: 31032853.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis. AU - Gignac,Sarah J, AU - Hosseini-Farahabadi,Sara, AU - Akazawa,Takashi, AU - Schuck,Nathan J, AU - Fu,Katherine, AU - Richman,Joy M, PY - 2019/01/21/received PY - 2019/03/26/revised PY - 2019/03/28/accepted PY - 2019/4/30/pubmed PY - 2020/3/13/medline PY - 2019/4/30/entrez SP - 2395 EP - 2414 JF - Human molecular genetics JO - Hum Mol Genet VL - 28 IS - 14 N2 - Heterozygous missense mutations in several genes in the WNT5A signaling pathway cause autosomal dominant Robinow syndrome 1 (DRS1). Our objective was to clarify the functional impact of a missense mutation in WNT5A on the skeleton, one of the main affected tissues in RS. We delivered avian replication competent retroviruses (RCAS) containing human wild-type WNT5A (wtWNT5A), WNT5AC83S variant or GFP/AlkPO4 control genes to the chicken embryo limb. Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter and 200% wider than controls. In contrast, bone dimensions in wtWNT5A limbs were slightly affected (20% shorter, 25% wider) but ossification occurred on schedule. The dysmorphology of bones was established during cartilage differentiation. Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of disrupted planar cell polarity (PCP) mechanisms. Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability. Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted, compared to wtWNT5A. Thus, in the chicken and human, RS phenotypes are produced from the C83S mutation, even though the variant protein is less abundant than wtWNT5A. We conclude the variant protein has dominant-negative effects on chondrogenesis leading to limb abnormalities. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/31032853/Robinow_syndrome_skeletal_phenotypes_caused_by_the_WNT5AC83S_variant_are_due_to_dominant_interference_with_chondrogenesis_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddz071 DB - PRIME DP - Unbound Medicine ER -