ArticleProceedings of the National Academy of Sciences of the United States of America2015
Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 64 citations in OpenAlex.
- DNA methylation marks associated with body composition in children from India and the Gambia: findings from the EMPHASIS study.Clinical epigenetics · 2026Article
- Methyltransferase complex subunit METTL3 maintains genome stability of erythroid cells via MTHFD1-mediated nucleotide biosynthesis.The Journal of clinical investigation · 2026Article
- Photorespiration is linked to DNA methylation by formate as a one-carbon source.Nature plants · 2026Article
- A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis.Science (New York, N.Y.) · 2025Article
- 5-Formyltetrahydrofolate in a Cohort of Pregnant Women Following Folic Acid Supplementation.ACS omega · 2025Article
- Biological, dietetic and pharmacological properties of vitamin BNPJ science of food · 2025Review
- MTHFD1 Regulates Autophagy to Promote Growth and Metastasis in Colorectal Cancer via the PI3K-AKT-mTOR Signaling Pathway.Cancer medicine · 2024Article
- Regulatory mechanisms of one-carbon metabolism enzymes.The Journal of biological chemistry · 2023Review
- Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity.Genes & nutrition · 2023Article
- Pathogenesis of neural tube defects: The regulation and disruption of cellular processes underlying neural tube closure.WIREs mechanisms of disease · 2022Review
- Exploring the metabolic landscape of pancreatic ductal adenocarcinoma cells using genome-scale metabolic modeling.iScience · 2022Article
- Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Article
- Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.The American journal of clinical nutrition · 2020Article
- Deoxyuracil in DNA in health and disease.Current opinion in clinical nutrition and metabolic care · 2020Review
- Deoxyuracil in DNA and disease: Genomic signal or managed situation?DNA repair · 2019Review
- NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism.Nature metabolism · 2019Article
- The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1.Frontiers in genetics · 2019Review
- Cell cycle regulation of folate-mediated one-carbon metabolism.Wiley interdisciplinary reviews. Systems biology and medicine · 2018Review
- Nuclear Folate Metabolism.Annual review of nutrition · 2018Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been identified. The proband presented with SCID, megaloblastic anemia, and neurologic abnormalities, but the causal metabolic impairment is unknown. SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis. MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol. In this study, we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency. The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency.
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