Abstract
Neural Tube Defects (NTDs) are congenital malformations resulting from
abnormal embryonic development of the brain, spine, or spinal column.
The genetic etiology of human NTDs remains poorly understood despite
intensive investigation. CIC, homolog of the Capicua transcription
repressor, has been reported to interact with ataxin-1 (ATXN1) and
participate in the pathogenesis of spinocerebellar ataxia type 1. Our
previous study demonstrated that CIC loss of function (LoF) variants
contributed to cerebral folate deficiency by downregulating folate
receptor 1 (FOLR1) expression. Given the importance of folate transport
in neural tube formation, we hypothesized that CIC variants could
contribute to increased risk for NTDs by depressing embryonic folate
concentrations. In this study, we examined CIC variants from whole
genome sequencing (WGS) data of 140 isolated spina bifida cases and
identified 8 missense variants of CIC gene. We tested the pathogenicity
of the observed variants through multiple in vitro experiments. We
determined that CIC variants decreased FOLR1 protein level and planar
cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a
murine cell line (NIH3T3), CIC loss of function variants down regulated
PCP signaling. Taken together, this study provides evidence supporting
CIC as a risk gene for human NTD.