On this page
MTRR
5-methyltetrahydrofolate-homocysteine methyltransferase reductase
The MTRR gene provides instructions for making the methionine synthase reductase enzyme, which plays a key role in reactivating another enzyme essential for amino acid metabolism. The MTRR gene is responsible for producing methionine synthase reductase.
MTRR is located on the short (p) arm of chromosome 5, at band 5p15.31. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 5 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The MTRR gene, also known as 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, encodes an enzyme vital for a critical metabolic pathway. This enzyme helps maintain the activity of methionine synthase, which is involved in processing amino acids.
Disruptions to the MTRR gene's function can lead to impaired methionine synthesis and an accumulation of homocysteine, impacting various bodily systems. Understanding MTRR is important for carrier screening and investigating certain metabolic conditions.
What the gene does
The MTRR gene produces methionine synthase reductase, an enzyme required for the proper function of methionine synthase. Methionine synthase is involved in amino acid metabolism, specifically converting homocysteine to methionine. After a period of activity, methionine synthase becomes inactive.
Methionine synthase reductase's primary function is to reactivate methionine synthase, enabling it to continue its role in producing methionine. Without sufficient and functional methionine synthase reductase, the methionine synthase enzyme cannot be reset and therefore cannot efficiently process homocysteine, which can have downstream metabolic consequences.
Video: Genetics 101
Chromosome location
The MTRR gene is situated on chromosome 5, specifically at the position 5p15.31. This gene is found on the short (p) arm of chromosome 5, within band 15, sub-band 31. The precise location on the chromosome helps in mapping and understanding its genetic context.
Protein structure
The MTRR protein, methionine synthase reductase, consists of 698 amino acids. It features several distinct regions and domains crucial for its enzymatic activity. These include a Flavodoxin-like domain spanning amino acids 5-147, a Hinge region from amino acids 166-247, and an FAD-binding FR-type domain located between amino acids 271-533. These domains collectively contribute to the protein's ability to reactivate methionine synthase.
Key variants
Genetic variations within the MTRR gene can affect the function of the methionine synthase reductase enzyme. These changes can range from single amino acid alterations to mutations that lead to a truncated, non-functional protein. Such variants may impair the enzyme's ability to reactivate methionine synthase, leading to metabolic imbalances.
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.1129C>T | p.Arg377Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblE |
c.1373C>G | p.Ser458Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblE |
c.1418_1419del | p.Val473fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neural tube defects, folate-sensitive |
c.1475G>A | p.Trp492Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neural tube defects, folate-sensitive |
c.1554_1557+3del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Neural tube defects, folate-sensitive |
c.1674dup | p.Arg559Ter | Pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblE |
c.1677-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblE |
c.1953-6_1953-2del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Neural tube defects, folate-sensitive |
c.354_358del | p.Gly119fs | Pathogenic/Likely pathogenic | ★★☆☆ | MTRR-related disorder |
c.701dup | p.Leu235fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylcobalamin deficiency type cblE |
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
Variations in the MTRR gene are associated with inherited conditions, including homocystinuria. In individuals with homocystinuria related to MTRR, the enzyme's impaired function prevents methionine synthase from properly converting homocysteine to methionine. This can lead to an accumulation of homocysteine in the body. Specific variants within the MTRR gene have also been suggested to be associated with an increased risk of certain birth defects affecting brain and spinal cord development.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MTRR 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 MTRR gene is included in several UK NHS national genomic testing panels, reflecting its clinical significance. It is listed as 'green' on the Cytopenias and congenital anaemias, DDG2P, Intellectual disability, Rare anaemia (R92), and Undiagnosed metabolic disorders panels. It is also featured on the Likely inborn error of metabolism panel (R98), indicating its role in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MTRR gene?
The MTRR gene provides instructions for making the enzyme methionine synthase reductase. This enzyme is crucial for reactivating methionine synthase, which is involved in converting the amino acid homocysteine to methionine.
What conditions are associated with MTRR gene variations?
Variations in the MTRR gene are primarily associated with homocystinuria, a condition characterised by the impaired conversion of homocysteine to methionine. Some MTRR variants have also been linked to an increased risk of certain birth defects.
Why is MTRR important for amino acid metabolism?
MTRR is essential for amino acid metabolism because its encoded enzyme, methionine synthase reductase, reactivates methionine synthase. Methionine synthase is the enzyme directly responsible for processing homocysteine into methionine, a vital step in maintaining metabolic balance.
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
- Vilaseca MA, Vilarinho L, Zavadakova P. CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. Journal of inherited metabolic disease. 2003. PMID: 12971424
- Carmel R, Green R, Rosenblatt DS. Update on cobalamin, folate, and homocysteine. Hematology. American Society of Hematology. Education Program. 2003. PMID: 14633777
- 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
- Zavadakova P, Fowler B, Zeman J. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. Journal of inherited metabolic disease. 2002. PMID: 12555939
- Hobbs CA, Sherman SL, Yi P. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. American journal of human genetics. 2000. PMID: 10930360
- Wilson A, Leclerc D, Rosenblatt DS. Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. Human molecular genetics. 1999. PMID: 10484769