What Is the MTHFD1 Gene Mutation?

What Is the MTHFD1 Gene Mutation?

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder
Last updated:

What is MTHFD1?

The MTHFD1 gene provides instructions for making an enzyme called C1-tetrahydrofolate synthase (also known as MTHFD1). MTHFD1 is a trifunctional enzyme that catalyzes three different reactions in the folate cycle. It helps make important building blocks for DNA and supports the methionine cycle, which is involved in processing proteins and other vital functions in the body.1


Specifically, the MTHFD1 enzyme:

  • Converts formate and THF into 10-formylTHF
  • Converts 10-formylTHF into 5,10-methenylTHF (and back again)
  • Converts 5,10-methenylTHF into 5,10-methyleneTHF


Each of these forms plays a role in key chemical reactions needed for cell growth and repair.

What is an MTHFD1 gene mutation?

A mutation on the MTHFD1 gene can lead to a deficiency in the MTHFD1 enzyme and impair its function. Because MTHFD1 is involved in the conversion of folate cofactors, which are essential for methylation and synthesising DNA, a MTHFD1 gene mutation can have a major impact on overall health.


Mutations can impair the synthesis of thymidylate, an important building block for DNA. This may lead to increased DNA uracil levels and genome instability.2

Symptoms of MTHFD1 deficiency and health implications

There are many genetic variants in the MTHFD1 gene, each with potentially different health implications. The most common MTHFD1 variant is the homozygous form of MTHFD1 G1958A, also known as R653Q (or rs2236225). Current population studies in Europe show the frequency of a homozygous variant (two copies) is around 5-10% in Europeans3

Neural tube defects

The genotypes rs2236225 GG [normal], GA [single mutation], and AA [double mutation] (also referred to as 653RR [normal], 653RQ [single mutation], and 653QQ [double mutation]) have been studied for their potential links to folate-dependent birth defects.

Animal studies suggest that low folate levels combined with maternal MTHFD1 deficiency significantly increase the incidence of developmental delays, neural tube defects (NTDs), intrauterine growth restriction, and other abnormalities. Both folate deficiency and excessive folic acid supplementation increased rates of NTDs, indicating that either can disrupt normal development, possibly due to impaired methylation.

Other research suggests that the MTHFD1 SNP rs1076991 C>T alone isn’t a major risk factor for neural tube defects (NTDs), but the risk may increase when combined with another known variant, R653Q.5 This genotype in children is also associated with increased risk for heart defects, but further studies are required.6

Megaloblastic anemia

MTHFD1 plays an important role in making thymidylate (a building block of DNA) in the cell nucleus. MTHFD1 deficiency can impair this process, which may lead to megaloblastic anemia.7

Reduced methylation

Animal studies show that a 50% reduction in MTHFD1 impairs homocysteine remethylation, leading to lower S-adenosylmethionine (SAMe) levels, elevated homocysteine, and lower levels of methionine.8

Impaired MTHFD1 activity may reduce the body’s ability to deal with folate deficiency and to optimally respond to treatment with antifolates (i.e. methotrexate).9

Impairments to choline and methionine metabolism

The MTHFD1 gene may affect how the body uses folate, choline, and methionine. These nutrients are involved with methylation, detoxification, and the production of antioxidants like glutathione.

A study in mice found that MTHFD1 G1958A disrupted several metabolic pathways, especially the methionine cycle and choline metabolism. This led to lower methionine and higher homocysteine. Choline-derived methyl groups were used to compensate for reduced methylation. This has also been found in humans with certain MTHFD1 gene variations (SNPs).10  In other words, people with MTHFD1 variants may require more choline to support essential methylation processes, especially if they have low folate. Choline-rich foods such as eggs, liver, soy, and oily fish may help, but it’s important to talk to a healthcare professional or nutritionist first.

Serious health issues

Variants that significantly reduce or eliminate enzyme function and can cause severe health conditions are uncommon.11 These conditions have only been observed in fewer than 30% of reported cases and are typically linked to rare, loss-of-function mutations. They include severe combined immunodeficiency (SCID), thrombocytosis, hearing impairments, and pancytopenia (deficiency in red and white blood cells and platelets).12

Treatment of MTHFD1 deficiency

Choline

Methyl groups derived from choline can compensate for reduced methylation in people with certain MTHFD1 gene variations (SNPs). People with the G1958A variant were seven times more likely to develop choline deficiency within a month of a low-choline diet.13

Choline is an essential nutrient present in foods such as beef, liver, and soybeans.

Phosphatidylcholine is the main phospholipid of cellular membranes that supports cell function and the structure and fluidity of cell membranes. It is broken down to release free choline, which can then be used for other purposes, including synthesis of acetylcholine (a neurotransmitter involved in memory and learning).14 Phosphatidylcholine is present in lecithin, egg yolks, beef, chicken, milk, fish, and soybeans.

Methylfolate

Although there is limited research into methylfolate supplementation for MTHFD1, low folate is a common challenge of those with MTHFD1 variants due to poor folate metabolism. Methylfolate is the only form of folate that does not require further conversion in the body, which means it can bypass any metabolic defects.15

It should also be noted that folic acid may not be suitable for those with MTHFD1 variants. One study involving mice with the MTHFD1 R653Q variant found that moderate doses of folic acid during pregnancy resulted in a lower methylation potential in the mother and greater incidence of defects in embryos.16

Folinic acid (calcium folinate) is a bioavailable form of folate that can cross the blood-brain-barrier without further conversion. Folic acid may interfere with 5-MTHF by competing for the same receptors, potentially depleting folate levels further.17

What is the MTHFD1 gene mutation?

Key takeaways

  • Icon MTHFD1 is essential for converting folate into active forms needed for DNA synthesis, cell growth, repair, and processing proteins.
  • Icon Mutations in the MTHFD1 gene can disrupt these processes and have been linked to neural tube defects and megaloblastic anemia.
  • Icon Choline and methylfolate supplementation may help support methylation in people with certain MTHFD1 gene variants, while folic acid is generally not recommended.

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$39.00

  • Bioactive L-Methylfolate 3 Mg & Methylated B12
  • Great for Bypassing MTHFR Mutations
  • 3rd-Party Tested for Purity, Potency & Safety
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Frequently Asked Questions about MTHFD1

What does MTHFD1 do?

The MTHFD1 gene provides instructions for making the MTHFD1 enzyme, methylenetetrahydrofolate dehydrogenase. This enzyme helps carry out three consecutive steps to convert different forms of tetrahydrofolate (THF), the coenzyme derived from folate. This process is required to create purines and pyrimidines, the building blocks of DNA.

What are the symptoms of MTHFD1?

There are many different MTHFD1 variants (mutations) and most will not produce symptoms.
The most common variant may increase the risk of low folate and higher homocysteine levels.
Less common variants may increase the risk of neural tube defects and megaloblastic anemia.18

What is MTHFD1 gene mutation?

A mutation on the MTHFD1 gene may lead to a deficiency or impairment to the MTHFD1 enzyme. However, the impact on one’s health depends on the severity of the enzyme deficiency, and severe deficiencies are not as common.

References

  1. National Library of Medicine; "Gene"; www.ncbi.nlm.nih.gov

    https://www.ncbi.nlm.nih.gov/gene

  2. Martha S. Field, Elena Kamynina, David Watkins, David S. Rosenblatt, Patrick J. Stover; "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis"; Proceedings of the National Academy of Sciences; 2015 Jan

    https://www.pnas.org/doi/10.1073/pnas.1414555112

  3. Karen E Christensen, Charles V Rohlicek, Gregor U Andelfinger, Jacques Michaud, Jean-Luc Bigras, Andrea Richter, Robert E Mackenzie, Rima Rozen; "The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects"; Human mutation; 2009 Feb

    https://pubmed.ncbi.nlm.nih.gov/18767138/

  4. Christensen Karen E, Bahous Renata H, Hou Wenyang, Deng Liyuan, Malysheva Olga V, Arning Erland, Bottiglieri Teodoro, Caudill Marie A, Jerome-Majewska Loydie A, Rozen Rima; "Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects"; The Journal of Nutrition; 2018 Apr

    https://www.sciencedirect.com/science/article/pii/S0022316622108084

  5. Nicola Carroll, Faith Pangilinan, Anne M Molloy, James Troendle, James L Mills, Peadar N Kirke, Lawrence C Brody, John M Scott, Anne Parle-McDermott; "Analysis of the MTHFD1 promoter and risk of neural tube defects"; Human genetics; 2009 Apr

    https://pubmed.ncbi.nlm.nih.gov/19130090/

  6. Karen E Christensen, Charles V Rohlicek, Gregor U Andelfinger, Jacques Michaud, Jean-Luc Bigras, Andrea Richter, Robert E Mackenzie, Rima Rozen; "The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects"; Human mutation; 2009 Feb

    https://pubmed.ncbi.nlm.nih.gov/18767138/

  7. Martha S. Field, Elena Kamynina, David Watkins, David S. Rosenblatt, Patrick J. Stover; "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis"; Proceedings of the National Academy of Sciences; 2015 Jan

    https://www.pnas.org/doi/full/10.1073/pnas.1414555112

  8. Martha S. Field, Elena Kamynina, David Watkins, David S. Rosenblatt, Patrick J. Stover; "Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis"; Proceedings of the National Academy of Sciences; 2015 Jan

    https://www.pnas.org/doi/10.1073/pnas.1414555112

  9. Maja Krajinovic; "MTHFD1 Gene: Role in Disease Susceptibility and Pharmacogenetics"; Pharmacogenomics; 2008

    https://www.tandfonline.com/doi/full/10.2217/14622416.9.7.829

  10. Martha S Field, Kelsey S Shields, Elena V Abarinov, Olga V Malysheva, Robert H Allen, Sally P Stabler, Jessica A Ash, Barbara J Strupp, Patrick J Stover, Marie A Caudill; "Reduced MTHFD1 Activity in Male Mice Perturbs Folate- and Choline-Dependent One-Carbon Metabolism as Well as Transsulfuration"; The Journal of nutrition; 2012 Nov

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3521460

  11. Gawa Bidla, David Watkins, Céline Chéry, D Sean Froese, Courtney Ells, Matin Kerachian, Avi Saskin, Karen E Christensen, Brian M Gilfix, Jean-Louis Guéant, David S Rosenblatt; "Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency"; Molecular genetics and metabolism; 2020 Jul

    https://pubmed.ncbi.nlm.nih.gov/32414565/

  12. HGNC,NCBIGENE,ORPHANET,OMIM, Mendelian Rare Disease Search Engine; "MTHFD1 gene related symptoms and diseases"; mendelian; 2025

    https://www.mendelian.co/genes/mthfd

  13. Martin Kohlmeier, Kerry-Ann da Costa, Leslie M. Fischer, Steven H. Zeisel; "Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans"; Proceedings of the National Academy of Sciences; 2005 Nov

    https://www.pnas.org/doi/10.1073/pnas.0504285102

  14. Elsa Sanchez-Lopez, Zhenyu Zhong, Alexandra Stubelius, Shannon R Sweeney, Laela M Booshehri, Laura Antonucci, Ru Liu-Bryan, Alessia Lodi, Robert Terkeltaub, Juan Carlos Lacal, Anne N Murphy, Hal M Hoffman, Stefano Tiziani, Monica Guma, Michael Karin; Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production"; Cell metabolism; 2020 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6675591

  15. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine; 2022 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

  16. Karen E Christensen, Wenyang Hou, Renata H Bahous, Liyuan Deng, Olga V Malysheva, Erland Arning, Teodoro Bottiglieri, Marie A Caudill, Loydie A Jerome-Majewska, Rima Rozen; "Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development"; The American journal of clinical nutrition; 2016 Nov

    https://pubmed.ncbi.nlm.nih.gov/27707701/

  17. Bedson E, Bell D, Carr D; "Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation."; Health Technology Assessment, 2014 Jul

    https://www.ncbi.nlm.nih.gov/books/NBK262310/

  18. Jian Wu, Yihua Bao, Xiaolin Lu, Lihua Wu, Ting Zhang, Jin Guo, Jian Yang; "Polymorphisms in MTHFD1 Gene and Susceptibility to Neural Tube Defects: A Case-Control Study in a Chinese Han Population with Relatively Low Folate Levels"; Medical science monitor : international medical journal of experimental and clinical research; 2015 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC4566945/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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