Year: 2022
Type: article
Study design: Observational Study
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.
Source: Human Mutation
DOI: 10.1002/humu.24460
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: California Department of Public Health, Hamad Medical Corporation, University of Texas at Austin, National Institutes of Health, Centers for Disease Control and Prevention, Department of Mechanical Engineering, University of Texas at Austin, Weill Cornell Medicine - Qatar, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Risk Genes and Environmental Interactions in Neural Tube Defects, G2632263588, CALIFORNIA CENTER OF BD-STEPS II FINDING CAUSES AND PREVENTIVES OF BIRTH DEFECTS, Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects, Training Program in Developmental and Stem Cell Biology, CALIFORNIA CENTER OF THE NBDPS - FINDING CAUSES AND PREVENTIVES OF BIRTH DEFECTS, Epigenome Interactions in Complex Neurogenetic Disorders, Folic Acid, Parental Mutation Rates and the Risk for Neural Tube Defects, Training in Precision Environmental Health Sciences
OpenAlex ID: W4294295932