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TRMU
tRNA mitochondrial 2-thiouridylase
TRMU is located on the long (q) arm of chromosome 22, at band 22q13.31. Arm ratio per GRCh38 - banding schematic.
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Overview
TRMU is located on chromosome 22 and encodes a specialised enzyme called tRNA mitochondrial 2-thiouridylase. This protein functions exclusively within mitochondria, where it carries out a precise chemical modification of transfer RNA (tRNA) molecules. Transfer RNAs serve as adaptors during protein synthesis, matching the genetic code in messenger RNA to the correct amino acids. The modification performed by TRMU involves adding a sulphur-containing group to a specific position on certain mitochondrial tRNAs, which helps maintain the accuracy and efficiency of mitochondrial protein production. Because mitochondria generate most of the cell's energy through a process called oxidative phosphorylation, disruptions to mitochondrial protein synthesis can have widespread effects on cellular function, particularly in tissues with high energy demands such as the liver, brain, and muscle.
What the gene does
The TRMU protein catalyses the addition of a thiouridine modification at the wobble position of certain mitochondrial tRNAs. This chemical change involves incorporating a sulphur atom into the uridine base at position 34 of the tRNA anticodon loop, creating 2-thiouridine. The modification is particularly important for tRNAs that decode codons ending in adenine or guanine, as the sulphur group enhances the stability of base pairing between the tRNA anticodon and the messenger RNA codon during translation. By strengthening these interactions, TRMU helps ensure that the correct amino acids are incorporated into mitochondrial proteins at the proper positions. The enzyme requires iron-sulphur clusters and other cofactors to carry out its catalytic function. Mitochondria contain their own small genome that encodes 13 essential protein subunits of the respiratory chain complexes, and accurate translation of these proteins is critical for energy metabolism. The TRMU enzyme therefore plays an indirect but vital role in supporting cellular respiration by maintaining the fidelity of mitochondrial protein synthesis.
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Chromosome location
TRMU is situated on the long arm of chromosome 22 at position 13.31, designated as 22q13.31. The gene spans this chromosomal region and contains the coding sequence for a 421-amino-acid protein. Like other nuclear genes encoding mitochondrial proteins, TRMU is transcribed and translated in the cell's nucleus and cytoplasm, after which the protein is imported into mitochondria through a targeting sequence. The chromosomal location at 22q13 places TRMU among other genes in a region that has been associated with various genetic conditions when structural abnormalities occur.
Protein structure
The TRMU protein comprises 421 amino acids and contains several functionally important regions. Specific residues mediate interaction with target base in tRNA at amino acids 96-98, while two separate regions interact with tRNA more broadly at amino acids 171-173 and 334-335. These interaction sites position the enzyme to recognise and bind its tRNA substrates precisely, enabling the chemical modification to occur at the correct nucleotide position. The carboxy-terminal region from amino acids 395-421 is disordered, meaning it lacks a fixed three-dimensional structure. Disordered regions often participate in regulatory interactions or provide flexibility that allows the protein to adopt different conformations during its catalytic cycle. The combination of structured tRNA-binding regions and flexible segments supports the enzyme's specialised role in mitochondrial tRNA modification.
Key variants
Genetic variants in TRMU can alter the enzyme's ability to modify mitochondrial tRNAs effectively. Changes that reduce enzymatic activity may impair mitochondrial protein synthesis, leading to deficiencies in respiratory chain function. The spectrum of TRMU variants includes missense changes that substitute individual amino acids, as well as nonsense and frameshift variants that truncate the protein or disrupt its reading frame. The functional consequences of specific variants depend on their location within the protein and their effect on enzymatic activity, tRNA binding, or protein stability.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in TRMU have been associated with mitochondrial disorders characterised by impaired energy metabolism. These conditions can present with a range of clinical features reflecting the widespread dependence of tissues on mitochondrial function. Liver dysfunction is a common manifestation, with some affected individuals experiencing transient infantile liver failure or cholestasis during early development. Neurological features, metabolic disturbances, and multi-system involvement may also occur. The variability in presentation reflects differences in the specific variants present, the degree of residual enzyme activity, and individual genetic and environmental modifying factors. Because mitochondrial energy production is essential for numerous physiological processes, TRMU-related conditions can affect multiple organ systems to varying degrees.
No disease links recorded for this gene in our reference set.
UK clinical status
Within the NHS Genomic Medicine Service, TRMU appears on multiple clinical gene panels reflecting its role in mitochondrial and metabolic disease. The gene holds green (high evidence) classification on panels including Mitochondrial disorders, Possible mitochondrial disorder - nuclear genes (R63), Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders. TRMU is also included on panels for Mitochondrial liver disease, including transient infantile liver failure (R317), Neonatal cholestasis, and Cholestasis (R171). These panel memberships indicate that NHS laboratories may analyse TRMU when investigating patients with clinical presentations suggestive of mitochondrial dysfunction, particularly when liver involvement or metabolic abnormalities are present. The broad panel representation reflects the diverse phenotypic spectrum associated with mitochondrial tRNA modification defects.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the TRMU gene do?
TRMU encodes an enzyme that modifies specific transfer RNA molecules inside mitochondria by adding a sulphur-containing chemical group. This modification helps ensure accurate protein synthesis within mitochondria, supporting cellular energy production.
How are TRMU variants inherited?
TRMU variants associated with mitochondrial disorders typically follow an autosomal recessive inheritance pattern, meaning an affected individual inherits one altered copy from each parent. Carrier parents usually do not show symptoms themselves.
Why is TRMU important for mitochondrial function?
The TRMU enzyme maintains the accuracy of mitochondrial protein synthesis by modifying tRNAs that decode genetic instructions. Because mitochondria produce most cellular energy, disruptions to this process can impair energy metabolism and affect tissues with high energy demands.