CIC Missense Variants Contribute to Susceptibility for Spina Bifida

Authors

Xiao Han
Xuanye Cao
Vanessa Aguiar-Pulido
Wei Yang
Menuka Karki
Paula Andrea Pimienta Ramirez
Robert M Cabrera
Ying Linda Lin
Bogdan J Wlodarczyk
Gary M Shaw
M Elizabeth Ross
Cuilian Zhang
Richard H Finnell
Yunping Lei

Publication Date

12-1-2022

Journal

Human Mutation

DOI

10.1002/humu.24460

PMID

36054333

PMCID

PMC9772115

PubMedCentral® Posted Date

12-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Female, Humans, Mice, Pregnancy, Folate Receptor 1, Folic Acid, Mutation, Missense, Neural Tube Defects, NIH 3T3 Cells, Spinal Dysraphism, HeLa Cells, Repressor Proteins, CIC, NTDs, PCP signaling pathway, FOLR1

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 the cerebral folate deficiency syndrome 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 eight missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased the 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 downregulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD.

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