rs1801394 — MTRR A66G

MTRR — The B12 Recycling Enzyme

Methionine synthase reductase (MTRR) is a critical support enzyme in the methylation cycle. Its job is to reactivate methionine synthase (MTR) after it becomes oxidized and inactive during normal operation. Think of MTRR as the maintenance crew that keeps the methylation assembly line running.

The Mechanism

MTR uses methylcobalamin ¹¹ Methylcobalamin: the methyl-carrying form of vitamin B12, one of two bioactive cobalamin forms (active B12) as a cofactor to convert homocysteine to methionine. During this reaction, B12 occasionally becomes oxidized to an inactive form. MTRR steps in to reduce (reactivate) the B12, restoring MTR function. The A66G variant (rs1801394) causes an isoleucine-to-methionine substitution ²² Isoleucine-to-methionine substitution at position 22 of the protein (p.Ile22Met) at position 22, which reduces MTRR's ability to perform this reactivation efficiently. ClinVar classifies this as benign given its very high population frequency, though functional studies show reduced enzyme affinity for MTR.

The Evidence

The GG genotype has been associated with elevated homocysteine³³ associated with elevated homocysteine
Gueant-Rodriguez RM et al. MTRR and neural tube defect risk, 2003 levels in several studies, though the effect is typically smaller than that of MTHFR C677T. A meta-analysis⁴⁴ meta-analysis
Botto LD & Yang Q. Meta-analysis of one-carbon metabolism variants and NTD risk, 2006 found that the G allele modestly increases the risk of neural tube defects and is associated with altered DNA methylation patterns. The variant is extremely common — about 50% of Europeans are heterozygous (AG) and 25% are homozygous (GG).

B12 Form Matters

Because MTRR affects B12 reactivation, the form of B12 you consume may matter. Hydroxocobalamin is the preferred form because it can be readily converted to both methylcobalamin (for methylation) and adenosylcobalamin ⁵⁵ Adenosylcobalamin is the mitochondrial form of B12, essential for energy metabolism via the citric acid cycle (for energy metabolism). Cyanocobalamin (the cheapest supplement form) requires additional conversion steps and may be less efficient if your MTRR is compromised.

Practical Implications

If you carry the G allele, ensuring adequate B12 intake becomes more important than average. This is especially relevant for vegetarians and vegans who may already be at risk for B12 deficiency. Active B12 forms (hydroxocobalamin, methylcobalamin, adenosylcobalamin) may be preferable to cyanocobalamin.

Interactions

MTRR works in concert with MTR (rs1805087) — both variants affect B12 handling in the methylation cycle. Combined with MTHFR variants (rs1801133), impairment at multiple points compounds the effect on overall methylation capacity.