Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations
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AbstractCongenital 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.
All Author(s) ListFeng 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., Watanabe K., Wu Z., Posey J.E., Ikegawa S., Lupski J.R., Cheung J.P.Y., Zhang T.J., Gao B., Wu N.
Journal nameProceedings of the National Academy of Sciences USA
Year2024
Month4
Volume Number121
Issue Number18
PublisherNational Academy of Sciences
Article numbere2310283121
ISSN0027-8424
eISSN1091-6490
LanguagesEnglish-United Kingdom
Keywordscongenital scoliosis, congenital vertebral malformation, planar cell polarity (PCP), somite, VANGL1/2
