G
Genetic Archaeology
GENETIC ARCHAEOLOGY // PROFILE

MTRR

Methionine Synthase Reductase

CHR 5
5p15.31

Overview

MTRR encodes the enzyme methionine synthase reductase. This enzyme is essential for the function of methionine synthase (MTR), as it maintains Vitamin B12 (cobalamin) in its active state or reactivates it.

📍 Chromosomal Position

5p15.31 (Chromosome 5)

🧬 Gene Category

Vitamins

🔬 Inheritance

Complex

📊 Prevalence

G allele ~50%

Function & Significance

MTRR plays a supportive but critical role in one-carbon metabolism:

  • B12 Regeneration: Reduces oxidized cobalamin (B12) back to its active state (methylcobalamin).
  • MTR Support: Without active B12, the MTR enzyme cannot convert homocysteine into methionine.
  • Maintenance of Methylation: Ensures the availability of methionine for DNA methylation.

🤝 Teamwork

MTRR is the “technician” who repairs the tool (Vitamin B12) of the “worker” (MTR). If MTRR works slower, Vitamin B12 “wears out” faster, and the entire process (homocysteine breakdown) comes to a standstill.

🧬 Relevant SNPs

The A66G variant (I22M):

rs1801394
5:7918805
Allele 1

A

/

Allele 2

G

Significance: A66G (I22M) – Isoleucine → Methionine at position 22

• AA: Normal enzyme efficiency

• GG: Reduced efficiency in B12 reactivation

• AG: Intermediate

⚠️ Impact of the G Variant

G carriers (especially GG) may have:

  • Increased Vitamin B12 requirement: To compensate for lower efficiency.
  • Sensitivity to B12 deficiency: Symptoms of deficiency may appear earlier.
  • Synergistic effects: The risk of high homocysteine increases significantly if MTR or MTHFR variants are also present.

Note: Approx. 25% of the population has the GG genotype and approx. 50% are AG carriers.

💊 Recommendations for G Carriers

Securing cobalamin supply:

  • Vitamin B12 Focus: Pay attention to optimal intake through diet or supplements.
  • Bioavailability: Methylcobalamin is the already “active” form and can be advantageous for MTRR-G carriers.
  • Regular testing: Determination of Holo-Transcobalamin (active B12) and homocysteine levels.

📚 Data Sources

  • OMIM: #602568 – Online Mendelian Inheritance in Man
  • dbSNP: rs1801394 – SNP Database (NCBI)
  • ClinVar: Clinical variants for MTRR (NCBI)
  • Journal of Medical Genetics: Studies on MTRR A66G

Last Update: February 2026

Biological Function

MTRR plays a crucial role in regenerating Vitamin B12. Vitamin B12 is a cofactor for methionine synthase (MTR). During the reaction, the cobalamin center of B12 can become oxidized, rendering the enzyme inactive. MTRR reduces oxidized cobalamin using electrons from NADPH back to its active state, allowing homocysteine metabolism to continue.

Associated Conditions

Hyperhomocysteinemia Neural Tube Defects Cardiovascular Diseases Megaloblastic Anemia
Molecular Analysis

Analyzed Markers

rs1801394 Risk Factor
Pos: 5:7918805 | Alleles: A/G

A66G (I22M) - G-allele (Met): Reduced efficiency in B12 regeneration. Increases requirement for Vitamin B12, especially in combination with MTR or MTHFR variants.