Details:

Alternative Title:
Hum Mutat
Personal Author:
Han, Xiao ; Cao, Xuanye ; Aguiar-Pulido, Vanessa ; Yang, Wei ; Karki, Menuka ; ... More +
Han, Xiao ; Cao, Xuanye ; Aguiar-Pulido, Vanessa ; Yang, Wei ; Karki, Menuka ; Ramirez, Paula Andrea Pimienta ; Cabrera, Robert M. ; Lin, Ying Linda ; Wlodarczyk, Bogdan J. ; Shaw, Gary M. ; Ross, M. Elizabeth ; Zhang, Cuilian ; Finnell, Richard H. ; Lei, Yunping Less -
Description:
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.
Subjects:
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Animals Female Folate Receptor 1 Folic Acid HeLa Cells Humans Mice Mutation, Missense Neural Tube Defects NIH 3T3 Cells Pregnancy Repressor Proteins Spinal Dysraphism
Source:
Hum Mutat. 43(12):2021-2032
Pubmed ID:
36054333
Pubmed Central ID:
PMC9772115
Document Type:
Journal Article
Funding:
R01 HD100535/HD/NICHD NIH HHSUnited States/ ; P30 ES030285/ES/NIEHS NIH HHSUnited States/ ; P01 HD067244/HD/NICHD NIH HHSUnited States/ ; T32 HD060600/HD/NICHD NIH HHSUnited States/ ; U01 DD000489/DD/NCBDD CDC HHSUnited States/ ; ... More +
R01 HD100535/HD/NICHD NIH HHSUnited States/ ; P30 ES030285/ES/NIEHS NIH HHSUnited States/ ; P01 HD067244/HD/NICHD NIH HHSUnited States/ ; T32 HD060600/HD/NICHD NIH HHSUnited States/ ; U01 DD000489/DD/NCBDD CDC HHSUnited States/ ; R01 NS076465/NS/NINDS NIH HHSUnited States/ ; T32 ES027801/ES/NIEHS NIH HHSUnited States/ ; R01 HD081216/HD/NICHD NIH HHSUnited States/ Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:acbd8ca1c4fe7a887266bb8177f1f7f5971e56ad47a31eca97e9ca4a4982db13
Download URL:
https://stacks.cdc.gov/view/cdc/123021/cdc_123021_DS1.pdf
File Type:

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