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ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 72-77

Homozygous mutation in the MTHFS gene may contribute to the development of cerebral folate deficiency syndrome


1 Center for Precision Environmental Health; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030-3411, USA
2 Center for Precision Environmental Health; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030-3411, USA
3 Center for Precision Environmental Health; Department of Molecular and Human Genetics; Department of Molecular and Cellular Biology; Department of Medicine, Baylor College of Medicine, Houston, Texas 77030-3411, USA

Correspondence Address:
Richard H Finnell
Center for Precision Environmental Health, Baylor College of Medicine, One Baylor Plaza, BCM 946, Houston, Texas 77030-3411
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.288022

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Objective: The purpose of this study was to examine the role of rare variants in the one-carbon metabolic pathway in the etiology of the cerebral folate deficiency (CFD) syndrome. The CFD syndrome is a neurometabolic syndrome identified by low concentrations of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF) in spite of near-normal peripheral folate levels resulting in neurodevelopmental disorders. Methods: The localized folate metabolism impairments in CFD are thought to be either the result of mutations in genes responsible for folate transport or folate turnover through degradation. Genes that have been previously implicated in the etiology of CFD include folate receptor alpha-1 (FOLR1), dihydrofolate reductase, proton-coupled folate transporter, and capicua. We performed whole-exome sequencing (WES) analysis of a CFD patient that revealed 99 novel missense mutations, of which 21 were classified as damaging mutations through the Poly-Phen2 prediction algorithm. In vitro functional studies were conducted by transient transfection of wild-type and mutant MTHFS into HEK293T cells to determine the impact of the variants on enzyme activity. Results: Of the damaging variants identified in the WES studies, we focused on the gene coding for the enzyme 5,10-methenyl-tetrahydrofolate synthetase (MTHFS). This enzyme catalyzes the production of methenyl THF which is subsequently converted to 5-MTHF. The CFD patient described within was found to carry a homozygous mutation, c.101G>T (p.R34L, rs200058464) in MTHFS, while the parents of the proband are heterozygotes for the MTHFS gene, and the healthy sibling is not a carrier. Conclusion: The mutant allele displayed a 50% reduction in luciferase activity (P < 0.05), suggesting that homozygous loss of the MTHFS gene may play a significant role in the development of CFD.


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