On this page
MTR
5-methyltetrahydrofolate-homocysteine methyltransferase
The MTR gene provides instructions for making the enzyme methionine synthase, which plays a crucial role in amino acid metabolism by converting homocysteine to methionine. The MTR gene is essential for producing methionine synthase, an enzyme vital for the body's metabolic processes.
MTR is located on the long (q) arm of chromosome 1, at band 1q43. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The MTR gene, also known as 5-methyltetrahydrofolate-homocysteine methyltransferase, provides the genetic blueprint for synthesising the enzyme methionine synthase. This enzyme is central to a key metabolic pathway that involves amino acids, the fundamental building blocks of proteins. Specifically, methionine synthase is responsible for converting homocysteine, a potentially harmful amino acid if accumulated, into methionine, an essential amino acid required for numerous cellular functions.
Disruptions in the MTR gene's function can impact this critical conversion process, leading to metabolic imbalances. These imbalances are often associated with conditions that affect the body's ability to properly metabolise certain amino acids.
What the gene does
The methionine synthase enzyme, encoded by the MTR gene, catalyses a vital step in the folate and methionine cycles. Its primary function is the remethylation of homocysteine to methionine. This reaction is crucial because methionine is used in various cellular processes, including protein synthesis, transmethylation reactions, and the formation of S-adenosylmethionine (SAM), a universal methyl donor.
To perform its function effectively, methionine synthase relies on methylcobalamin, a specific form of vitamin B12, acting as a cofactor. The enzyme also interacts with methionine synthase reductase (encoded by the MTRR gene), which helps maintain the enzyme's active state. This enzymatic activity ensures the proper processing of amino acids, contributing to overall metabolic health and preventing the build-up of homocysteine.
Video: Genetics 101
Chromosome location
The MTR gene is situated on chromosome 1, specifically located on the long arm at position 43, denoted as 1q43. This precise genomic address helps in identifying and studying the gene's position within the human genome.
Protein structure
The methionine synthase protein, comprising 1265 amino acids, features several distinct functional domains. These include the Hcy-binding domain, spanning amino acids 19-338, which is involved in binding homocysteine. The Pterin-binding domain, located from amino acids 371-632, facilitates the interaction with methyltetrahydrofolate. Two B12-binding domains are present: an N-terminal one from amino acids 662-759 and another from 772-907, both crucial for binding the methylcobalamin cofactor. Finally, the AdoMet activation domain, found between amino acids 923-1265, is involved in activating the enzyme.
Key variants
Variations within the MTR gene can alter the structure and function of the methionine synthase enzyme. These genetic changes, often referred to as mutations or pathogenic variants, can affect how efficiently the enzyme converts homocysteine to methionine. Such alterations may lead to reduced enzyme activity or even the production of a non-functional enzyme.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1200dup | p.Val401fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.1941dup | p.Arg648fs | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.1992_1993insATCA | p.Glu665fs | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.2100dup | p.Tyr701fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.2404C>T | p.Arg802Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.2474-1G>C | - | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.2799_2803del | p.Ala935fs | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.3439C>T | p.Arg1147Ter | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.609+1088G>A | - | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
c.866-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblG |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the MTR gene are associated with an increased risk of specific health conditions, notably homocystinuria. Homocystinuria is a group of inherited disorders characterised by the body's inability to process certain amino acids, leading to an accumulation of homocysteine in the blood and urine. Other disorders, including certain birth defects, have also been linked to specific MTR gene variants.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MTR variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The MTR gene is included in several NHS Genomic Medicine Service national test panels. These panels cover conditions such as Cytopenias and congenital anaemias, Intellectual disability, Likely inborn error of metabolism, Rare anaemia, and Undiagnosed metabolic disorders, indicating its recognised clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MTR gene?
The MTR gene provides instructions for making the methionine synthase enzyme. This enzyme's main role is to convert the amino acid homocysteine into methionine, a crucial step in amino acid metabolism.
What happens if the MTR gene has a variant?
If the MTR gene has a pathogenic variant, it can lead to a less functional or non-functional methionine synthase enzyme. This can disrupt the conversion of homocysteine to methionine, potentially causing conditions like homocystinuria.
How does vitamin B12 relate to the MTR gene?
The methionine synthase enzyme, encoded by the MTR gene, requires methylcobalamin, a form of vitamin B12, as a cofactor to function properly. Vitamin B12 is essential for the enzyme to catalyse the conversion of homocysteine to methionine.
References
- Guéant-Rodriguez RM, Rendeli C, Namour B. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans. Neuroscience letters. 2003. PMID: 12812837
- Bosco P, Guéant-Rodriguez RM, Anello G. Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. American journal of medical genetics. Part A. 2003. PMID: 12923861
- Carmel R, Green R, Rosenblatt DS. Update on cobalamin, folate, and homocysteine. Hematology. American Society of Hematology. Education Program. 2003. PMID: 14633777
- Watkins D, Ru M, Hwang HY. Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. American journal of human genetics. 2002. PMID: 12068375
- Doolin MT, Barbaux S, McDonnell M. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. American journal of human genetics. 2002. PMID: 12375236