TRMU – Acute Infantile Liver Failure due to Synthesis Defect of mtDNA-Encoded Proteins

The nuclear gene TRMU encodes a tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase responsible for 2-thiolation of mitochondrial tRNAs, a modification essential for mitochondrial DNA-encoded protein synthesis. Biallelic pathogenic variants in TRMU underlie acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, a transient neonatal hepatic disorder featuring spontaneous recovery in early infancy (PMID:33485800).

The condition is inherited in an autosomal recessive manner, with six unrelated infants presenting within the first months of life with acute hepatic failure, persistent lactic acidosis (HP:0004898) and hypoglycemia (HP:0001943) (PMID:33485800). Parental testing confirmed segregation of biallelic variants such as c.37_48dup (p.Asp16_Ser17insGlyGlyValAsp). No additional affected relatives have been reported.

A recurrent missense variant c.680G>C (p.Arg227Thr) was identified in two siblings: one died from complications, while prenatal diagnosis and early L-cysteine supplementation in the other achieved full recovery without transplantation (PMID:30740308). Population prevalence remains undefined.

The variant spectrum includes in-frame duplications, missense substitutions and small indels predicted to disrupt catalytic activity. Loss-of-function and hypomorphic alleles lead to deficient mt-tRNA thiolation, impaired mitochondrial translation and respiratory complex dysfunction.

Functional studies in liver-specific Mtu1 knockout mice recapitulate key human features, demonstrating loss of 2-thiolation, impaired mitochondrial translation and elevated lactate; L-cysteine supplementation restores respiratory complex activities and ameliorates histopathology (PMID:27689697). In vitro, L-cysteine rescues cytochrome c oxidase activity in patient fibroblasts with TRMU deficiency by enhancing mt-tRNA thiolation (PMID:23814040).

These data support a loss-of-function mechanism for TRMU variants and demonstrate that cysteine availability is rate-limiting for enzyme activity. Exogenous cysteine supplementation offers a low-risk therapeutic approach that may improve survival and reduce disease severity.

Early genetic testing for TRMU in infants with unexplained lactic acidosis and hypoglycemia can guide timely initiation of cysteine therapy, potentially preventing progression to liver failure and reducing the need for transplantation.

References

• Adenine AI • 2025 • TRMU deficiency causes transient infantile liver failure PMID:33485800
• Molecular Genetics and Metabolism Reports • 2019 • L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency PMID:30740308
• PLoS Genetics • 2016 • Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury PMID:27689697
• Human Molecular Genetics • 2013 • Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency PMID:23814040

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