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
  • Female
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Carrier Proteins*
  • Membrane Proteins*/genetics
  • Membrane Proteins*/metabolism
  • Scoliosis/congenital
  • Scoliosis/genetics
  • Scoliosis/metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Wnt Signaling Pathway/genetics
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism
  • Cell Polarity*/genetics
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Animals
  • Spine*/abnormalities
  • Spine*/metabolism
  • Mice
  • Genetic Predisposition to Disease
(all 23)
PubMed
38669183 Full text @ Proc. Natl. Acad. Sci. USA
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
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
congenital kyphosisTAS
scoliosisTAS
1 - 2 of 2
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Sequence Targeting Reagents
Fish
Fish
AB + MO1-vangl2
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Antibodies
No data available
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
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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.