PUBLICATION
Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations
- Authors
- Feng, X., Ye, Y., Zhang, J., Zhang, Y., Zhao, S., Mak, J.C.W., Otomo, N., Zhao, Z., Niu, Y., Yonezawa, Y., Li, G., Lin, M., Li, X., Cheung, P.W.H., Xu, K., Takeda, K., Wang, S., Xie, J., Kotani, T., Choi, V.N.T., Song, Y.Q., Yang, Y., Luk, K.D.K., Lee, K.S., Li, Z., Li, P.S., Leung, C.Y.H., Lin, X., Wang, X., Qiu, G., DISCO (Deciphering disorders Involving Scoliosis and COmorbidities) study group, Watanabe, K., Japanese Early Onset Scoliosis Research Group, Wu, Z., Posey, J.E., Ikegawa, S., Lupski, J.R., Cheung, J.P.Y., Zhang, T.J., Gao, B., Wu, N.
- ID
- ZDB-PUB-240427-8
- Date
- 2024
- Source
- Proceedings of the National Academy of Sciences of the United States of America 121: e2310283121e2310283121 (Journal)
- Registered Authors
- Keywords
- VANGL1/2, congenital scoliosis, congenital vertebral malformation, planar cell polarity (PCP), somite
- MeSH Terms
-
- Animals
- Carrier Proteins*
- Cell Polarity*/genetics
- Female
- Genetic Predisposition to Disease
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Membrane Proteins*/genetics
- Membrane Proteins*/metabolism
- Mice
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Scoliosis/congenital
- Scoliosis/genetics
- Scoliosis/metabolism
- Spine*/abnormalities
- Spine*/metabolism
- Wnt Signaling Pathway/genetics
- Zebrafish*/embryology
- Zebrafish*/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38669183 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Feng, X., Ye, Y., Zhang, J., Zhang, Y., Zhao, S., Mak, J.C.W., Otomo, N., Zhao, Z., Niu, Y., Yonezawa, Y., Li, G., Lin, M., Li, X., Cheung, P.W.H., Xu, K., Takeda, K., Wang, S., Xie, J., Kotani, T., Choi, V.N.T., Song, Y.Q., Yang, Y., Luk, K.D.K., Lee, K.S., Li, Z., Li, P.S., Leung, C.Y.H., Lin, X., Wang, X., Qiu, G., DISCO (Deciphering disorders Involving Scoliosis and COmorbidities) study group, Watanabe, K., Japanese Early Onset Scoliosis Research Group, Wu, Z., Posey, J.E., Ikegawa, S., Lupski, J.R., Cheung, J.P.Y., Zhang, T.J., Gao, B., Wu, N. (2024) Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations. Proceedings of the National Academy of Sciences of the United States of America. 121:e2310283121e2310283121.
Abstract
Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping