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Neurogenetics
Original research
CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression
  1. Xuanye Cao1,
  2. Annika Wolf2,
  3. Sung-Eun Kim3,
  4. Robert M. Cabrera1,
  5. Bogdan J. Wlodarczyk1,
  6. Huiping Zhu4,
  7. Margaret Parker3,
  8. Ying Lin1,
  9. John W. Steele1,5,
  10. Xiao Han1,
  11. Vincent Th Ramaekers6,
  12. Robert Steinfeld2,7,
  13. Richard H. Finnell3,8,9,
  14. Yunping Lei1
  1. 1 Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
  2. 2 Department of Pediatric Neurology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
  3. 3 Department of Pediatrics, University of Texas at Austin, Austin, Texas, USA
  4. 4 Department of Nutritional Sciences, University of Texas at Austin Dell Medical School, Austin, Texas, USA
  5. 5 Institute for Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA
  6. 6 Department of Pediatric Neurology, University Hospital Center Liège, Liège, Belgium
  7. 7 University Children’s Hospital Zurich, Zurich, Switzerland
  8. 8 Center for Precision Environmental Health, Departments of Molecular and Cellular Biology and Medicine, Houston, Texas, USA
  9. 9 Departments of Molecular and Human Genetics and Medicine, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr. Yunping Lei, Baylor College of Medicine, Houston, Texas, USA; yunpinglei{at}gmail.com; Dr. Richard H. Finnell; richard.finnell{at}bcm.edu; Dr. Robert Steinfeld; Robert.Steinfeld{at}kispi.uzh.ch

Abstract

Background Cerebral folate deficiency (CFD) syndrome is characterised by a low concentration of 5-methyltetrahydrofolate in cerebrospinal fluid, while folate levels in plasma and red blood cells are in the low normal range. Mutations in several folate pathway genes, including FOLR1 (folate receptor alpha, FRα), DHFR (dihydrofolate reductase) and PCFT (proton coupled folate transporter) have been previously identified in patients with CFD.

Methods In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis on eight CFD trios and identified eight de novo mutations in seven trios.

Results Notably, we found a de novo stop gain mutation in the capicua (CIC) gene. Using 48 sporadic CFD samples as a validation cohort, we identified three additional rare variants in CIC that are putatively deleterious mutations. Functional analysis indicates that CIC binds to an octameric sequence in the promoter regions of folate transport genes: FOLR1, PCFT and reduced folate carrier (Slc19A1; RFC1). The CIC nonsense variant (p.R353X) downregulated FOLR1 expression in HeLa cells as well as in the induced pluripotent stem cell (iPSCs) derived from the original CFD proband. Folate binding assay demonstrated that the p.R353X variant decreased cellular binding of folic acid in cells.

Conclusion This study indicates that CIC loss of function variants can contribute to the genetic aetiology of CFD through regulating FOLR1 expression. Our study described the first mutations in a non-folate pathway gene that can contribute to the aetiology of CFD.

  • clinical genetics
  • genetics
  • nutrition and metabolism
  • genome-wide

Data availability statement

Data are available on reasonable request. Data are available from the corresponding author on request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2020-106987

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    Data availability statement

    Data are available on reasonable request. Data are available from the corresponding author on request.

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    Footnotes

    • XC, AW and S-EK contributed equally.

    • Contributors YL, AW, S-EK, RS and RHF conceived and designed the experiments. RC performed FOLR1 autoantibody detection assay and patient fibroblast cell culture. BW provided critical input to the project. XC and HZ assisted in the genetic analysis of the whole-exome sequencing data. MP performed human iPSCs generation. JS performed qRT-PCR. XH performed overexpression and co-IP assays. RHF, RS, XC and YL recruited patients, acquired clinical data or analysed whole exome sequencing or Sanger sequencing results. YL, XC, RC, AW, S-EK, RS and RHF drafted the original manuscript and all authors assisted in editing the manuscript.

    • Funding This project was supported in part by grants NIH R01 HD081216 and HD083809 to RHF.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.