MTR Gene Test (Methionine Synthase)

The MTR gene encodes methionine synthase, also known as 5 methyltetrahydrofolate homocysteine methyltransferase, a cobalamin dependent enzyme that catalyses the remethylation of homocysteine to methionine. This reaction uses 5 methyltetrahydrofolate as a methyl donor and methylcobalamin, a form of vitamin B12, as a cofactor within the folate and one carbon metabolism network.

MTR works closely with the MTRR gene, which encodes methionine synthase reductase, an enzyme that keeps methionine synthase in its active state so it can continue processing homocysteine. Loss of function mutations in MTR can cause rare, severe methylcobalamin deficiencies with marked homocysteine elevation, while more common polymorphisms, such as A2756G, tend to produce subtler shifts in enzyme activity and risk profiles.

MTR sits at a critical junction where homocysteine is recycled back into methionine, closing the loop of the methylation cycle and supplying methionine for conversion to S adenosylmethionine, the body's universal methyl donor. This process supports DNA and RNA synthesis, DNA methylation, neurotransmitter production, phospholipid formation, and many other methylation dependent reactions that underpin cardiovascular, neurological, and reproductive health.

When MTR activity is impaired by genetics, B12 deficiency, or disruptions in folate metabolism, homocysteine can accumulate and methionine availability may fall, which can strain methylation capacity and subtly influence vascular integrity, neurodevelopment, and cellular repair. The degree of impact depends on how much MTR function is reduced and how well buffered the system is by other enzymes, nutrient status, and lifestyle factors.

MTR contributes to three interconnected domains: homocysteine regulation, methylation capacity, and B12 and folate dependent DNA synthesis. Shifts in this enzyme can influence long term patterns in cardiovascular risk, neurocognitive function, fertility and pregnancy outcomes, and some cancer susceptibility profiles, especially when combined with other methylation related variants and suboptimal nutrition.

Research on MTR polymorphisms, including A2756G, has explored associations with conditions such as coronary artery disease, stroke, male infertility, and certain cancers through mechanisms involving homocysteine, DNA methylation, and one carbon metabolism. The real world impact of these variants is generally modest and context dependent, with homocysteine levels, B12 and folate status, kidney function, and overall metabolic health typically exerting a larger influence on day to day risk than genotype alone.

It is easy to assume that MTR testing and homocysteine testing overlap completely, but they capture different layers of your biology. Homocysteine is a dynamic blood marker that reflects how your methylation cycle and B vitamin status are performing right now, whereas MTR testing looks at inherited changes that may influence how easily homocysteine rises when B12 or folate status is suboptimal.

This distinction matters because you can carry an MTR variant and still have homocysteine within a healthy range when B12, folate, and broader lifestyle factors are well supported. Conversely, homocysteine can be elevated in someone with a "typical" MTR genotype due to B12 or folate deficiency, kidney disease, hypothyroidism, certain medications, or lifestyle patterns, all of which often respond well to targeted clinical and behavioural support.

The influence of MTR variants is shaped far more by your environment and physiology than by the gene alone. Several modifiable factors can buffer or amplify MTR related tendencies.

• Vitamin B12 and folate status: MTR is both B12 and folate dependent, so adequate intake and absorption of these nutrients can neutralise much of the functional impact of reduced enzyme activity. Low B12, low folate, malabsorption, restrictive diets, or long term use of certain medications can make the same MTR variant more clinically relevant.
• MTRR and other methylation genes: MTR does not work in isolation. Variants in MTRR, MTHFR, and other one carbon metabolism genes can combine with MTR polymorphisms to shape homocysteine handling and methylation balance, which means looking at the wider network is often more informative than focusing on a single gene.
• Metabolic and cardiovascular health: Chronic kidney disease, diabetes, metabolic syndrome, and hypothyroidism can raise homocysteine independently of MTR and, when combined with MTR variants, can increase vascular strain. Addressing these conditions and improving overall metabolic health usually moves the needle more than the genotype itself.
• Medications and toxin exposures: Drugs that interfere with folate or B12 pathways, such as some anticonvulsants, metformin, proton pump inhibitors, or high dose nitrous oxide exposure, can worsen functional B12 status and increase homocysteine in people with vulnerable methylation pathways. Genotype information can support more personalised monitoring and cofactor support.
• Pregnancy, fertility, and life stage: During preconception and pregnancy, the demand for methylation and DNA synthesis rises, and MTR function becomes particularly relevant for homocysteine control and adequate methyl group supply. Age related shifts in B12 absorption and folate intake can also change how MTR variants express over the life course.
• Dietary patterns and lifestyle: Diets low in natural folate and B12 sources, smoking, high alcohol intake, and low physical activity can all push homocysteine upward and strain methylation networks, making MTR related effects more visible. In contrast, nutrient dense diets, regular movement, and good sleep support methylation whether or not you carry an MTR variant.

Yes, and that is common. Many people with MTR polymorphisms, including A2756G, never develop clear gene specific symptoms and discover their status only through comprehensive DNA panels or methylation focused testing.

Symptoms often attributed to "methylation issues," such as fatigue, low mood, brain fog, or headaches, are non specific and can arise from iron deficiency, thyroid dysfunction, sleep problems, psychological stress, or other conditions that deserve thorough assessment. Severe MTR related defects causing homocystinuria and methylcobalamin deficiency are rare, usually present early in life, and are distinct from the common polymorphisms reported on standard gene panels.

Common MTR genotypes mainly differ in how much they alter methionine synthase activity and how strongly they influence homocysteine and methylation, especially when B vitamin status is not optimised. Understanding your pattern can help tailor B12 and folate support, monitoring strategy, and lifestyle choices rather than labelling any genotype as "good" or "bad."

• Reference or "typical" genotypes: Individuals without function altering MTR variants generally have full enzyme capacity, so homocysteine levels and methylation performance depend more on nutrition, kidney function, thyroid status, and lifestyle than on MTR itself.
• Heterozygous carriers (for example one A2756G variant): These genotypes often show small, context dependent effects on enzyme function and homocysteine, which are frequently buffered by adequate B12 and folate intake. Many people in this group maintain healthy methylation with general lifestyle support.
• Homozygous or multiple risk variants: Having two copies of certain MTR variants or carrying multiple methylation related polymorphisms can reduce enzyme efficiency more substantially and make homocysteine rise more easily when B vitamin status slips. Even in this group, appropriate nutrition, lifestyle support, and clinical monitoring can often maintain homocysteine in a healthy range.

For DNA based MTR testing, preparation is simple because genotype does not change from day to day with meals, movement, or sleep. The key is selecting the right test panel and aligning timing with any accompanying blood biomarkers you plan to track over time.

Standalone MTR genotyping using blood or saliva does not require fasting, since it analyses stable DNA sequence rather than dynamic blood levels. If MTR is bundled with tests such as homocysteine, lipids, glucose, or other methylation related markers, your clinician or testing provider may recommend specific fasting windows or collection times so future results are easier to compare.

An MTR test is most useful when the results will influence how you personalise B12 and folate support, interpret persistent homocysteine elevation, or design long term cardiovascular and methylation strategies. It is less helpful when done in isolation without access to homocysteine, B12, folate, and broader clinical context.

• Unexplained elevated homocysteine: If homocysteine stays high despite apparently adequate folate and B12 intake, MTR genotyping can clarify whether reduced methionine synthase activity might be contributing and whether more tailored cofactor support or investigation is needed.
• Cardiovascular and metabolic risk planning: For individuals with a personal or family history of cardiovascular disease or metabolic syndrome, MTR testing alongside MTHFR, MTRR, and homocysteine can add nuance to risk assessment and support a more personalised prevention plan.
• Fertility, pregnancy, and recurrent pregnancy loss: In people planning pregnancy or with a history of recurrent miscarriage or neural tube defect affected pregnancy, MTR testing can provide extra context to folate and B12 strategies, complementing standard prenatal guidance.
• Complex B12 and methylation patterns: When B12 related labs, neurological symptoms, or response to supplementation are hard to interpret, MTR genotyping can be one helpful piece, particularly when combined with MTRR, homocysteine, and methylmalonic acid testing.