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MTHFD1
methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1
MTHFD1 is located on the long (q) arm of chromosome 14, at band 14q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
MTHFD1 encodes methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1, a multifunctional protein central to folate-dependent one-carbon metabolism. The enzyme coordinates three sequential catalytic activities that convert tetrahydrofolate derivatives into forms required for nucleotide biosynthesis and amino acid metabolism. Because rapidly dividing cells, particularly immune cells and developing neural tissue, depend heavily on these metabolic pathways, disruptions in MTHFD1 function can have profound consequences. Pathogenic variants in this gene follow an autosomal recessive inheritance pattern, meaning two altered copies are required for disease manifestation.
What the gene does
The MTHFD1 protein functions as a trifunctional enzyme operating within the cytoplasm, where it processes folate cofactors required for transferring one-carbon units between metabolic pathways. The dehydrogenase activity catalyses the NADP-dependent oxidation of methylenetetrahydrofolate to methenyltetrahydrofolate. The cyclohydrolase activity then converts methenyltetrahydrofolate to formyltetrahydrofolate. Finally, the synthetase domain catalyses the ATP-dependent synthesis of formyltetrahydrofolate from formate and tetrahydrofolate. Together, these reactions generate intermediates essential for purine and thymidylate synthesis, which are building blocks of DNA and RNA. The protein also contributes to methionine regeneration and other methylation-dependent processes. Disruption of any of the three enzymatic activities can impair nucleotide production, particularly affecting cells with high proliferation rates such as developing lymphocytes and neural progenitors.
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Chromosome location
MTHFD1 is located on the long arm of chromosome 14 at position 23.3 (14q23.3). This chromosomal region contains multiple genes involved in metabolic processes. The gene spans approximately 64 kilobases of genomic DNA and comprises 28 exons that together encode the 935-amino acid protein.
Protein structure
The MTHFD1 protein comprises 935 amino acids organised into two principal functional regions. The methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (D/C) domain occupies amino acids 2 through 291, housing the catalytic machinery for the first two enzymatic activities. The formyltetrahydrofolate synthetase domain spans amino acids 310 through 935 at the C-terminal end, responsible for the ATP-dependent ligation reaction. This modular architecture allows the protein to channel substrates efficiently through the three-step reaction sequence, with the physical proximity of active sites facilitating metabolic flux through the folate cycle.
Key variants
Pathogenic variants in MTHFD1 are rare but can severely disrupt folate-dependent metabolism when present in both gene copies. Most disease-causing changes are missense variants that impair one or more of the three enzymatic activities, though nonsense and frameshift variants have also been reported. The specific consequences of a variant often depend on which catalytic domain is affected and the degree of residual enzyme activity retained.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.146C>T | p.Ser49Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia |
c.153_154del | p.Ile53fs | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia |
c.517C>T | p.Arg173Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia |
c.673G>T | p.Glu225Ter | Pathogenic | ★★☆☆ | Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia |
c.727+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia |
c.1231C>T | p.Gln411Ter | Pathogenic | ★☆☆☆ | not provided |
c.316G>T | p.Glu106Ter | Pathogenic | ★☆☆☆ | not provided |
c.677G>A | p.Trp226Ter | Pathogenic | ★☆☆☆ | not provided |
c.886G>T | p.Glu296Ter | Pathogenic | ★☆☆☆ | not provided |
c.924del | p.Asn308fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in MTHFD1 have been associated with severe combined immunodeficiency and megaloblastic anaemia, reflecting the critical role of folate metabolism in lymphocyte development and red blood cell production. Some affected individuals also present with neurological features including developmental delay and structural brain abnormalities. The clinical spectrum appears variable, likely influenced by the specific variants inherited and the extent to which they compromise enzymatic function. Because the protein supports fundamental cellular processes, complete loss of function is thought to be incompatible with survival.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MTHFD1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
MTHFD1 is included on the NHS Genomic Medicine Service PanelApp in the Primary immunodeficiency or monogenic inflammatory bowel disease panel with green classification (version R15), reflecting clinical validity for genetic testing in patients with relevant immunological presentations. The gene also appears on the COVID-19 research panel with green status, indicating interest in its potential role in immune response variability during infection.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is MTHFD1-related disease inherited?
MTHFD1-related conditions follow an autosomal recessive pattern, meaning an individual must inherit a pathogenic variant from both parents to be affected. Carriers, who have one altered copy and one working copy, typically do not show symptoms but can pass the variant to their children.
Why does MTHFD1 have three different enzyme activities?
The MTHFD1 protein evolved to catalyse three consecutive reactions in the folate cycle within a single polypeptide chain. This trifunctional arrangement allows cells to process folate intermediates efficiently without requiring three separate enzymes, improving metabolic coordination and reducing the complexity of pathway regulation.
Can folate supplementation help individuals with MTHFD1 variants?
The effectiveness of folate supplementation depends on the specific variant and residual enzyme activity. While some individuals may benefit from increased substrate availability, pathogenic variants that eliminate enzyme function are unlikely to respond to supplementation alone. Any consideration of supplementation should be discussed with a healthcare provider familiar with the individual's genetic and clinical profile.