MTHFR Gene: Methylenetetrahydrofolate Reductase
Key enzyme in folate metabolism, linked to homocysteine regulation and multiple disorders
Gene Information Card
| Symbol | MTHFR |
|---|---|
| Full Name | Methylenetetrahydrofolate Reductase |
| Gene Type | Protein coding |
| Chromosomal Location | 1p36.22 |
| NCBI Gene ID | 4524 ncbi.nlm.nih.gov/gene/4524 |
| Ensembl ID | ENSG00000177000 |
| UniProt ID | P42898 |
| OMIM ID | 607093 |
| HGNC ID | 7436 |
| Aliases | MTHFR, methylenetetrahydrofolate reductase (NAD(P)H) |
Description
The MTHFR gene encodes methylenetetrahydrofolate reductase, a cytoplasmic enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. This reaction is critical for folate metabolism, DNA synthesis, and methylation. Common polymorphisms (e.g., C677T, A1298C) reduce enzyme activity and are associated with elevated homocysteine levels, neural tube defects, cardiovascular disease, and other conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Homocystinuria due to MTHFR deficiency | Loss-of-function mutations cause severe enzyme deficiency, leading to homocysteine accumulation and methionine depletion. | OMIM #236250 |
| Neural tube defects (maternal MTHFR variants) | Reduced enzyme activity impairs folate metabolism, increasing risk of spina bifida and anencephaly in offspring. | NCBI Gene, ClinVar |
| Cardiovascular disease | C677T variant associated with mild hyperhomocysteinemia, a risk factor for thrombosis and atherosclerosis. | ClinVar, OMIM |
| Megaloblastic anemia | Impaired folate metabolism due to MTHFR deficiency leads to ineffective erythropoiesis. | OMIM #236250 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | High |
| Kidney | 8.3 | Medium |
| Brain | 6.1 | Medium |
| Heart | 4.7 | Low |
| Lung | 3.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | 15.2 | High expression |
| HEK293 (embryonic kidney) | 9.8 | Moderate expression |
| SH-SY5Y (neuroblastoma) | 5.4 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| C677T (rs1801133) | Missense (Ala222Val) | 30-40% in general population | Reduces enzyme activity by ~35% in heterozygotes, ~70% in homozygotes; associated with hyperhomocysteinemia |
| A1298C (rs1801131) | Missense (Glu429Ala) | 20-30% in general population | Reduces enzyme activity moderately; compound heterozygotes with C677T may have further reduced activity |
| c.665C>T (p.Ala222Val) | Missense | Common | Same as C677T; thermolabile variant |
| c.1286A>C (p.Glu429Ala) | Missense | Common | Same as A1298C |
Mutation functional classification
Loss of Function (LOF)
Common missense variants (C677T, A1298C) reduce enzyme activity; rare nonsense/frameshift mutations cause complete loss of function leading to homocystinuria.
Gain of Function (GOF)
No known gain-of-function mutations reported.
Dominant Negative (DN)
Not described; MTHFR deficiency is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Folate metabolism (Reactome: R-HSA-196757)
• Methionine salvage pathway (KEGG: map00270)
• One-carbon metabolism (KEGG: map00670)
Protein Summary
MTHFR is a 656-amino acid flavoprotein that exists as a homodimer. It uses FAD as a cofactor and NAD(P)H as an electron donor to reduce 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The enzyme is thermolabile; the common C677T variant (Ala222Val) reduces activity and thermostability. MTHFR is essential for homocysteine remethylation and methylation reactions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MTHFR Knockout HEK293 Cell Line | EDJ-KQ2766 | Human | 4524 | Details Get a Quote |
| MTHFR Knockout A-549 Cell Line | EDJ-KQ23674 | Human | 4524 | Details Get a Quote |
| MTHFR Knockout HCT 116 Cell Line | EDJ-KQ23675 | Human | 4524 | Details Get a Quote |
| MTHFR Knockout HeLa Cell Line | EDJ-KQ23676 | Human | 4524 | Details Get a Quote |
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