PMID- 36054333
OWN - NLM
STAT- MEDLINE
DCOM- 20221221
LR  - 20231202
IS  - 1098-1004 (Electronic)
IS  - 1059-7794 (Print)
IS  - 1059-7794 (Linking)
VI  - 43
IP  - 12
DP  - 2022 Dec
TI  - CIC missense variants contribute to susceptibility for spina bifida.
PG  - 2021-2032
LID - 10.1002/humu.24460 [doi]
AB  - 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.
CI  - (c) 2022 Wiley Periodicals LLC.
FAU - Han, Xiao
AU  - Han X
AUID- ORCID: 0000-0001-6749-1877
AD  - Department of Reproductive Medicine Center, Henan Provincial People's Hospital, 
      People's Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Cao, Xuanye
AU  - Cao X
AUID- ORCID: 0000-0002-2181-3540
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Aguiar-Pulido, Vanessa
AU  - Aguiar-Pulido V
AUID- ORCID: 0000-0001-5248-6944
AD  - Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell 
      Medicine, New York, New York, USA.
AD  - Departments of Molecular and Human Genetics and Medicine, Baylor College of 
      Medicine, Houston, Texas, USA.
FAU - Yang, Wei
AU  - Yang W
AUID- ORCID: 0000-0002-2979-3425
AD  - Department of Computer Science, University of Miami, Coral Gables, Florida, USA.
FAU - Karki, Menuka
AU  - Karki M
AUID- ORCID: 0000-0002-1234-0024
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Ramirez, Paula Andrea Pimienta
AU  - Ramirez PAP
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Cabrera, Robert M
AU  - Cabrera RM
AUID- ORCID: 0000-0002-2998-0482
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Lin, Ying Linda
AU  - Lin YL
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Wlodarczyk, Bogdan J
AU  - Wlodarczyk BJ
AUID- ORCID: 0000-0002-8965-9957
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Shaw, Gary M
AU  - Shaw GM
AD  - Department of Computer Science, University of Miami, Coral Gables, Florida, USA.
FAU - Ross, M Elizabeth
AU  - Ross ME
AUID- ORCID: 0000-0001-6440-8089
AD  - Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell 
      Medicine, New York, New York, USA.
FAU - Zhang, Cuilian
AU  - Zhang C
AUID- ORCID: 0000-0002-5210-5272
AD  - Department of Reproductive Medicine Center, Henan Provincial People's Hospital, 
      People's Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
FAU - Finnell, Richard H
AU  - Finnell RH
AUID- ORCID: 0000-0002-5962-8754
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
AD  - Department of Pediatrics, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Lei, Yunping
AU  - Lei Y
AUID- ORCID: 0000-0003-1504-0884
AD  - Center for Precision Environmental Health, Department of Molecular and Cellular 
      Biology, Baylor College of Medicine, Houston, Texas, USA.
LA  - eng
GR  - R01 HD100535/HD/NICHD NIH HHS/United States
GR  - P30 ES030285/ES/NIEHS NIH HHS/United States
GR  - P01 HD067244/HD/NICHD NIH HHS/United States
GR  - T32 HD060600/HD/NICHD NIH HHS/United States
GR  - U01 DD000489/DD/NCBDD CDC HHS/United States
GR  - R01 NS076465/NS/NINDS NIH HHS/United States
GR  - T32 ES027801/ES/NIEHS NIH HHS/United States
GR  - R01 HD081216/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20220912
PL  - United States
TA  - Hum Mutat
JT  - Human mutation
JID - 9215429
RN  - 0 (Folate Receptor 1)
RN  - 935E97BOY8 (Folic Acid)
RN  - 0 (FOLR1 protein, human)
RN  - 0 (CIC protein, human)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Animals
MH  - Female
MH  - Humans
MH  - Mice
MH  - Pregnancy
MH  - Folate Receptor 1/genetics
MH  - Folic Acid
MH  - Mutation, Missense
MH  - *Neural Tube Defects/genetics
MH  - NIH 3T3 Cells
MH  - *Spinal Dysraphism/genetics
MH  - HeLa Cells
MH  - *Repressor Proteins/genetics
PMC - PMC9772115
MID - NIHMS1834314
OTO - NOTNLM
OT  - CIC
OT  - FOLR1
OT  - NTDs
OT  - PCP signaling pathway
COIS- COMPETING INTERESTS R.H.F., B.W.J. and R.M.C. formerly held leadership positions 
      with the now dissolved TeratOmic Consulting LLC. R.H.F. also receives travel 
      funds to attend editorial board meetings of the Journal of Reproductive and 
      Developmental Medicine published out of the Red Hospital of Fudan University. The 
      other authors declare no competing interests.
EDAT- 2022/09/03 06:00
MHDA- 2022/12/15 06:00
PMCR- 2023/12/01
CRDT- 2022/09/02 13:55
PHST- 2022/08/29 00:00 [revised]
PHST- 2021/11/12 00:00 [received]
PHST- 2022/08/30 00:00 [accepted]
PHST- 2022/09/03 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/09/02 13:55 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - 10.1002/humu.24460 [doi]
PST - ppublish
SO  - Hum Mutat. 2022 Dec;43(12):2021-2032. doi: 10.1002/humu.24460. Epub 2022 Sep 12.