MTRR A66G (rs1801394): Methionine Synthase Reductase

MTRR (methionine synthase reductase) is the enzyme that reactivates methionine synthase (MTR) after it becomes oxidized during normal function. The A66G variant (rs1801394) reduces MTRR's efficiency, potentially slowing the methylation cycle. This variant is very common and has been associated with elevated homocysteine, increased neural tube defect risk, and various health conditions when combined with other methylation variants.

Understanding MTRR's Role

MTRR maintains MTR in its active state:

The Problem: MTR Inactivation

• MTR requires vitamin B12 (methylcobalamin) as a cofactor
• During normal catalysis, B12 occasionally becomes oxidized
• Oxidized B12 renders MTR inactive
• Without reactivation, MTR can't convert homocysteine to methionine

MTRR's Solution

• MTRR uses SAM and FMN (flavin mononucleotide) to reduce oxidized B12
• This reactivates MTR so it can continue working
• Essential for maintaining methylation cycle flow
• Without MTRR, MTR activity would rapidly decline

The A66G Variant (Ile22Met)

• A allele: Isoleucine at position 22 - reference, normal function
• G allele: Methionine at position 22 - reduced efficiency (~4x less active)

Understanding Your Genotype

• A/A: Normal MTRR function - efficient MTR reactivation
• A/G: Heterozygous - moderately reduced MTRR activity
• G/G: Homozygous variant - significantly reduced activity

Methylation Impact

Slower MTR Reactivation

• G/G genotype = MTR spends more time inactive
• Reduces overall methylation cycle throughput
• May increase homocysteine levels
• Less methionine available for SAM production

Cascading Effects

• Reduced SAM affects 200+ methylation reactions
• DNA methylation may be impaired
• Neurotransmitter synthesis affected
• Detoxification pathways may be less efficient

Homocysteine Effects

Research Findings

• G/G genotype associated with elevated homocysteine in some studies
• Effect size varies by population and nutritional status
• Most pronounced when B12 or folate is low
• Combined with MTHFR variants, effects may be additive

Cardiovascular Implications

• Elevated homocysteine is a cardiovascular risk factor
• MTRR variants may contribute to this risk
• Optimizing B12 and folate can normalize homocysteine

Neural Tube Defects

NTD Risk Association

• MTRR A66G is one of the most studied NTD risk variants
• G/G genotype associated with 2-3x increased NTD risk in some studies
• Effect strongest when combined with low B12
• Maternal genotype most relevant

Prevention

• Adequate B12 before and during pregnancy
• Folate supplementation (standard recommendation)
• Test B12 levels - often overlooked compared to folate
• Consider methylated forms (methylcobalamin, methylfolate)

Gene Interactions

MTRR + MTR

• MTRR reactivates MTR - they work as a pair
• Variants in both = compounded methylation issues
• MTRR G/G + MTR G/G = significant methylation impairment

MTRR + MTHFR

• MTHFR provides 5-MTHF for MTR
• MTHFR C677T + MTRR A66G = additive risk
• Combined analysis recommended

The Complete Picture

Supporting MTRR Function

Vitamin B12

• Essential substrate for the MTRR reaction
• Methylcobalamin may be preferred form
• Consider higher doses for G/G genotype
• B12 shots/sublingual may improve absorption

Riboflavin (B2)

• MTRR requires FMN (derived from riboflavin)
• Adequate B2 supports MTRR function
• Often overlooked in methylation support
• RDA: 1.1-1.3 mg; some may benefit from more

Folate

• 5-MTHF is needed for the MTR reaction
• Supports overall methylation cycle
• Methylfolate preferred over folic acid

SAM Considerations

• SAM is required for MTRR reaction
• SAM supplementation controversial - can affect many pathways
• Better to support natural SAM production through B vitamins

Testing Recommendations

Blood Tests

• Homocysteine: Direct measure of methylation status
• Serum B12: Basic screening
• Methylmalonic acid: Functional B12 status
• Folate: Both serum and RBC folate

Target Values

• Homocysteine: Below 10 μmol/L optimal, below 12 acceptable
• B12: Upper half of normal range or higher
• Address elevated homocysteine with B vitamin optimization

Prevalence

• G allele frequency: ~45-55% - very common!
• G/G genotype: ~20-30% of population
• Key point: This is one of the most common methylation variants
• Population variation: Relatively consistent across ancestries

Clinical Significance

When MTRR Matters Most

• Combined with other methylation variants (MTHFR, MTR)
• Low B12 or folate status
• Pregnancy planning and early pregnancy
• Elevated homocysteine
• Unexplained fatigue, mood issues, or neurological symptoms

Testing with NutraHacker

NutraHacker's Complete Mutation Report analyzes MTRR along with MTHFR, MTR, and other methylation genes, providing a comprehensive view of your methylation genetics.

Frequently Asked Questions

I have G/G - is this serious?

The G/G genotype is very common (20-30% of people), so it's not inherently serious. However, it does mean your MTRR enzyme is less efficient. If you also have other methylation variants, eat a diet low in B vitamins, or have elevated homocysteine, it becomes more clinically relevant. Focus on adequate B12, folate, and B2 intake, and consider testing homocysteine levels.

Should I take methyl-B12 if I have this variant?

Methylcobalamin (methyl-B12) provides the ready-to-use form of B12 for MTR. For MTRR variants, ensuring adequate B12 is important, and methylcobalamin is a reasonable choice. However, cyanocobalamin also works for most people. The key is ensuring adequate B12 status however you achieve it. Higher doses may be beneficial for G/G individuals.

How does this interact with MTHFR?

MTHFR and MTRR variants can have additive effects on methylation. MTHFR reduces 5-MTHF production, while MTRR reduces MTR reactivation - both slow the methylation cycle through different mechanisms. If you have both MTHFR C677T and MTRR A66G variants, comprehensive B vitamin support becomes more important.

References

1. Gaughan DJ, et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001;157(2):451-456.
2. Wilson A, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. 1999;67(4):317-323.
3. Olteanu H, et al. Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein. J Biol Chem. 2001;276(38):35558-35563.