for spina bifida

Details

• Alternative Title:
  Hum Mutat
• Personal Author:
  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
• 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.
• Keywords:
  Animals CIC Female Folate Receptor 1 Folic Acid FOLR1 HeLa Cells Humans Mice Mutation, Missense Neural Tube Defects NIH 3T3 Cells NTDs PCP Signaling Pathway Pregnancy Repressor Proteins Spinal Dysraphism

  More +
• 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/ ; R01 NS076465/NS/NINDS NIH HHSUnited States/ ; T32 ES027801/ES/NIEHS NIH HHSUnited States/ ; R01 HD081216/HD/NICHD NIH HHSUnited States/
• Volume:
  43
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:2ff44884dce08f5200a0327322b77a665918f79d6c4e97c2c8eeaf715f04e0a16fa6c4d52183976713af240964c3d81610a7189fb81dfb10b471f1c7a11d319a
• Download URL:
  https://stacks.cdc.gov/view/cdc/123021/cdc_123021_DS1.pdf
• File Type:
  [PDF - 1.98 MB ]