Loss-of-function or gain-of-function variations in VINCULIN (VCL) are risk factors of human neural tube defects.

BACKGROUND Neural tube defects (NTDs) are severe birth defects resulting from the failure of neural tube closure during embryogenesis. Both genetic and environmental factors contribute to the occurrence of NTDs and the heritability of NTDs is approximately 70%. As a key component of focal adhesions, Vinculin (VCL) plays pivotal roles in cell skeleton remodeling and signal transduction. Vcl deficient mice displayed NTD, but how VCL variants contribute to human NTDs has not been addressed yet. METHODS We screened VCL variants in a Chinese cohort of 387 NTDs and 244 controls by targeted next-generation sequencing. RESULTS We identified four case-specific VCL variations (p.M209L, p.D256fs, p.L555V and p.R586Q). VCL p.D256fs and p.L555V are novel variations that have never been reported. Our analysis revealed that p.D256fs is a loss-of-function variant, while p.L555V showed a gain of function in planner cell polarity (PCP) pathway regulation and cell migration, probably due to its enhanced protein stability. CONCLUSION Our study reports human NTD specific novel variations in VCL and provides the functional evaluation of VCL variants related to the etiology of human NTDs.