What is the SHMT gene mutation?

Serine hydroxymethyltransferase (SHMT) is the enzyme required to convert the amino acid serine into glycine (another amino acid) by transferring part of the serine molecule to tetrahydrofolate (THF). This process creates 5,10-methylene-THF, the precursor to methylfolate.¹

There are two isoforms of the SHMT enzyme: SHMT1 (in the cytoplasm) and SHMT2 (in the mitochondria). The SHMT1 enzyme is encoded by the SHMT1 gene and plays a central role in the cytoplasm, supplying one-carbon units for nucleotide synthesis (purines and thymidylate) and for regenerating methionine. All of these processes are essential for DNA synthesis and methylation.²

SHMT1 converts tetrahydrofolic (THF) and serine into 5,10-methylenetetrahydrofolate (MeTHF) and the amino acid glycine. MeTHF is then converted to methylfolate by the MTHFR enzyme.

Genetic variants in MTHFR can impair the methylation cycle by reducing the conversion of 5,10-methylene-THF to methylfolate. Efficient SHMT1 activity is important because it helps maintain sufficient levels of 5,10-methylene-THF required for MTHFR to function properly. This is particularly relevant for people with MTHFR mutations.

Research suggests there are many DNA sequence variants in both the SHMT1 and MTHFR genes, though most don’t significantly affect enzyme function. However, certain variants in SHMT1 may alter the activity of the SHMT1 enzyme.³

A genetic variant (mutation) in the SHMT1 gene can influence how much of the enzyme is produced or how it functions.

The most common is the SHMT1 C1420T variant (rs1979277), with one study suggesting that the combined frequency of SHMT1 1420 CC and CT genotypes in Europe ranges from 83.3% to 91.3%.⁴ CT is a single copy of the variant (heterozygous), while TT is a double copy (homozygous).

SHMT2 deficiency is rare, with only a few cases reported.
The prevalence of each specific SHMT mutation can vary depending on the population being studied, and also by age and sex.

SHMT1 gene mutations may also lead to low folate levels and elevated homocysteine, which can be a risk factor for several health conditions.

• Low folate
  The SHMT1 enzyme helps produce 5,10-methylenetetrahydrofolate (5,10-MTHF), crucial for DNA synthesis and methylation. A SHMT mutation may reduce 5,10-MTHF production, disturbing one-carbon metabolism and the production of methylfolate.

• High homocysteine
  Some studies have noted high homocysteine in people with SHMT1 C1420T. However, the impact of SHMT1 on homocysteine depends on nutrient status, namely folate and B6, as well as co-existing genetic variants in folate metabolism, such as MTHFR C677T.
  SHMT1 C1420T carriers may have higher homocysteine levels due to poor folate metabolism. Low folate intake amplifies the risk associated with SHMT1 and MTHFR variants.⁵

• Cardiovascular disease
  The ‘T’ variant of the SHMT1 C1420T gene can increase cardiovascular risk, especially when combined with the ‘T’ variant of the MTHFR C677T gene.⁶
  This SHMT1 variant alters where the enzyme is located in the cell, reducing levels of MeTHF, a key molecule required by the MTHFR enzyme. When both variants are present, MeTHF levels decrease further and MTHFR activity is reduced, which may lead to a build-up of homocysteine, a known risk factor for heart disease.

• Slight risk of stroke
  Increased methylation of the SHMT1 gene can reduce expression of the gene, and this has been observed in patients affected by ischemic stroke. Ischemic stroke is commonly associated with elevated homocysteine levels, and some studies have identified a significantly higher level of SHMT1 methylation in patients who had suffered ischemic stroke.⁷

• Non-Hodgkin lymphoma
  The SHMT1 C1420T variant may be associated with a higher risk of developing  non-Hodgkin lymphoma, but further research is required.⁸

Methylfolate
Low folate and high homocysteine typically result from impaired folate metabolism. Supplementation with methylfolate (the active form of folate) has been shown to bypass genetic impairments in the folate pathway, restore folate levels and reduce homocysteine.⁹

Active vitamin B6
Pyridoxal 5′-phosphate (P5P), the active form of vitamin B6, acts as a cofactor in the methylation process. SHMT and thymidylate synthase required P5P to produce the nucleotide thymidylate (dTMP), an important building block of DNA involved in DNA synthesis and repair.
Studies in fruit flies show that PLP deficiency reduces SHMT activity by about 40%, which can lead to chromosome damage.¹⁰ However, PLP is essential for SHMT activity in all species. While further studies in humans are still pending, this gene–nutrient interaction may be relevant to human DNA repair and cellular health.¹¹