rs4659744 — MTR MTR variant

MTR rs4659744 — A Regulatory Signal in the B12-Dependent Remethylation Locus

Methionine synthase (MTR) performs one of the most critical reactions in one-carbon metabolism: it uses methylcobalamin (active vitamin B12) as a cofactor to transfer a methyl group from 5-methyltetrahydrofolate (methylfolate) onto homocysteine, converting it to methionine. This single reaction simultaneously clears homocysteine from the circulation, regenerates the folate pool, and produces the methionine needed to synthesize S-adenosylmethionine (SAM) — the universal methyl donor for hundreds of downstream reactions including DNA methylation, neurotransmitter synthesis, and phospholipid production.

rs4659744 sits deep within an MTR intron at chr1:236,896,158 (GRCh38)¹¹ chr1:236,896,158 (GRCh38)
Intronic position c.3598+608G>C in NM_000254.3; plus-strand notation, 608 nucleotides downstream of the nearest exon-intron boundary. Because it does not alter the protein sequence, its influence — if any — is likely regulatory: a modest shift in transcription efficiency, mRNA stability, or splicing that changes how much methionine synthase protein the cell produces under conditions of nutritional or oxidative stress.

The Mechanism

As a deep intronic variant, rs4659744 has no direct effect on MTR enzyme structure. The most plausible mechanistic model is that it tags a haplotype affecting MTR promoter activity or pre-mRNA processing. When B12 and folate supply is optimal, even a small reduction in MTR transcript level may be fully compensated — enzyme is not the rate-limiting factor. But when dietary B12 is marginal, MTRR (the B12-recycling enzyme encoded by rs1801394) is impaired, or MTHFR output is reduced, the buffer disappears and a quantitative shortfall in MTR activity can push homocysteine upward and trap methylfolate in its unusable form (the "methyl-folate trap" ²² When MTR is slow, 5-methylTHF cannot donate its methyl group and accumulates unusably, creating a functional folate deficiency even when total folate levels look normal).

The Evidence

The only published study specifically naming rs4659744 is a candidate gene analysis³³ candidate gene analysis
Levine AJ et al. Folate-associated one carbon metabolism genes and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev, 2010 of 1,805 colorectal cancer cases and 2,878 sibling controls from the Colon Cancer Family Registry. The C allele of rs4659744 was associated with significantly reduced colorectal cancer risk — but only among participants who did not use multivitamin supplements. In supplement users, the association disappeared. This interaction pattern is characteristic of folate-pathway variants in a post-folic-acid-fortification era: when supplements saturate the pathway, the modest regulatory effect of intronic variants becomes invisible; in the subset relying on diet alone, the signal re-emerges.

The study was not powered to characterize rs4659744 in isolation — it was testing 15 folate-pathway genes simultaneously, and the finding should be regarded as exploratory. No independent replication has been published. The evidence level is therefore emerging: a single, suggestive, hypothesis- generating finding from a well-designed candidate gene study.

Broader context from the MTR locus supports biological plausibility. The NHLBI Family Heart Study⁴⁴ NHLBI Family Heart Study
Jacques PF et al. Effects of MTR and MTRR polymorphisms on total plasma homocysteine. Atherosclerosis, 2003 (n=677) found no significant effect of common MTR variants on fasting homocysteine but noted a trend toward higher post-methionine-load homocysteine in MTR variant carriers, consistent with reserve capacity masking the genotype effect at rest.

Practical Actions

Because the evidence for rs4659744 specifically is emerging, the practical guidance mirrors the broader MTR locus recommendations: keep B12 status genuinely replete (not just within the lower end of the reference range), favour active B12 forms, and pair with methylfolate if MTHFR variants are also present. Periodic homocysteine testing is the most direct readout of whether the one-carbon cycle is running efficiently. For GC and CC carriers, the fact that the C allele showed protective signals in dietary-only populations suggests that adequate folate from whole foods — rather than high-dose synthetic folic acid — may be the most appropriate approach.

Interactions

MTR rs4659744 sits in the same gene as the missense variant rs1805087 (MTR A2756G / D919G) and the nearby intronic variant rs2275565. All three tag the same remethylation node. Their combined effect on MTR output is not well characterized, but carrying two or more MTR locus variants likely compounds the quantitative pressure on homocysteine conversion. Upstream, MTHFR C677T (rs1801133) controls methylfolate supply — the substrate MTR depends on. Downstream, MTRR A66G (rs1801394) controls B12 recycling — the cofactor MTR cannot work without. Weakness at two or more of these nodes is where clinically meaningful homocysteine elevation typically emerges.