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CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression


Cao, Xuanye; Wolf, Annika; Kim, Sung-Eun; Cabrera, Robert M; Wlodarczyk, Bogdan J; Zhu, Huiping; Parker, Margaret; Lin, Ying; Steele, John W; Han, Xiao; Ramaekers, Vincent T; Steinfeld, Robert; Finnell, Richard H; Lei, Yunping (2020). CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression. Journal of Medical Genetics:Epub ahead of print.

Abstract

<jats:bold>Background</jats:bold> 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 <jats:italic>FOLR1 (folate receptor alpha</jats:italic>, <jats:italic>FRα)</jats:italic>, <jats:italic>DHFR (dihydrofolate reductase)</jats:italic> and <jats:italic>PCFT (proton coupled folate transporter</jats:italic>) have been previously identified in patients with CFD.<jats:bold>Methods</jats:bold> 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.<jats:bold>Results</jats:bold> Notably, we found a de novo stop gain mutation in the <jats:italic>capicua</jats:italic> (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: <jats:italic>FOLR1</jats:italic>, <jats:italic>PCFT</jats:italic> and <jats:italic>reduced folate carrier (Slc19A1; RFC1</jats:italic>). The <jats:italic>CIC</jats:italic> 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.<jats:bold>Conclusion</jats:bold> This study indicates that <jats:italic>CIC</jats:italic> loss of function variants can contribute to the genetic aetiology of CFD through regulating <jats:italic>FOLR1</jats:italic> expression. Our study described the first mutations in a non-folate pathway gene that can contribute to the aetiology of CFD.

Abstract

<jats:bold>Background</jats:bold> 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 <jats:italic>FOLR1 (folate receptor alpha</jats:italic>, <jats:italic>FRα)</jats:italic>, <jats:italic>DHFR (dihydrofolate reductase)</jats:italic> and <jats:italic>PCFT (proton coupled folate transporter</jats:italic>) have been previously identified in patients with CFD.<jats:bold>Methods</jats:bold> 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.<jats:bold>Results</jats:bold> Notably, we found a de novo stop gain mutation in the <jats:italic>capicua</jats:italic> (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: <jats:italic>FOLR1</jats:italic>, <jats:italic>PCFT</jats:italic> and <jats:italic>reduced folate carrier (Slc19A1; RFC1</jats:italic>). The <jats:italic>CIC</jats:italic> 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.<jats:bold>Conclusion</jats:bold> This study indicates that <jats:italic>CIC</jats:italic> loss of function variants can contribute to the genetic aetiology of CFD through regulating <jats:italic>FOLR1</jats:italic> expression. Our study described the first mutations in a non-folate pathway gene that can contribute to the aetiology of CFD.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Genetics
Health Sciences > Genetics (clinical)
Uncontrolled Keywords:Genetics(clinical), Genetics
Language:English
Date:20 August 2020
Deposited On:27 Jan 2021 18:05
Last Modified:01 Mar 2021 16:21
Publisher:BMJ Publishing Group
ISSN:0022-2593
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1136/jmedgenet-2020-106987
PubMed ID:32820034

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