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CIC missense variants contribute to susceptibility for spina bifida
  • +11
  • Xiao Han,
  • Xuanye Cao,
  • Vanessa Aguiar-Pulido,
  • Wei Yang,
  • Menuka Karki,
  • Paula Andrea Pimienta Ramirez,
  • Robert Cabrera,
  • Ying Lin,
  • Bogdan Wlodarczyk,
  • Gary Shaw,
  • Margaret Ross,
  • Cuilian Zhang,
  • Richard Finnell,
  • Yunping Lei
Xiao Han
Henan Provincial People's Hospital

Corresponding Author:[email protected]

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Xuanye Cao
Baylor College of Medicine
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Vanessa Aguiar-Pulido
Weill Cornell Medical College
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Wei Yang
Stanford University School of Medicine
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Menuka Karki
Baylor College of Medicine
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Paula Andrea Pimienta Ramirez
Baylor College of Medicine
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Robert Cabrera
Baylor College of Medicine
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Ying Lin
Baylor College of Medicine
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Bogdan Wlodarczyk
Baylor College of Medicine
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Gary Shaw
Stanford University School of Medicine
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Margaret Ross
Weill Cornell Medicine
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Cuilian Zhang
Henan Provincial People's Hospital
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Richard Finnell
Baylor College of Medicine
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Yunping Lei
Baylor College of Medicine
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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.
06 Aug 2021Submitted to Human Mutation
20 Nov 2021Submission Checks Completed
20 Nov 2021Assigned to Editor
30 Nov 2021Reviewer(s) Assigned
14 Jan 2022Review(s) Completed, Editorial Evaluation Pending
20 Jan 2022Editorial Decision: Revise Major
08 Jul 20221st Revision Received
12 Jul 2022Submission Checks Completed
12 Jul 2022Assigned to Editor
10 Aug 2022Reviewer(s) Assigned
13 Aug 2022Review(s) Completed, Editorial Evaluation Pending
18 Aug 2022Editorial Decision: Revise Minor
29 Aug 20222nd Revision Received
30 Aug 2022Submission Checks Completed
30 Aug 2022Assigned to Editor
30 Aug 2022Review(s) Completed, Editorial Evaluation Pending
30 Aug 2022Editorial Decision: Accept
12 Sep 2022Published in Human Mutation. 10.1002/humu.24460