TRMU – Reversible Infantile Respiratory Chain Deficiency

Autosomal recessive biallelic variants in TRMU have been identified in patients with mitochondrial myopathy with reversible cytochrome C oxidase deficiency. In a cohort of eight infants with reversible infantile respiratory chain deficiency, two unrelated probands from two families harbored compound heterozygous or homozygous TRMU mutations, including frameshift and missense alleles such as c.835G>A (p.Val279Met) ([PMID:21931168]). These variants segregated with disease in affected siblings and unaffected parents, supporting autosomal recessive inheritance with segregation in two families.

Functional studies demonstrate that TRMU encodes a mitochondrial 2-thiouridylate methyltransferase essential for 2-thiouridylation of mt-tRNA^Glu, mt-tRNA^Lys, and mt-tRNA^Gln. Down-regulation of TRMU in patient-derived cells impairs 2-thiouridylation and exacerbates mitochondrial translation defects; supplementation with L-cysteine, a cofactor for TRMU activity, restores respiratory chain enzyme activities in vitro ([PMID:23814040]). These concordant functional data, together with the genetic findings, nominate TRMU deficiency as the molecular cause of a reversible respiratory chain myopathy and support targeted TRMU gene testing and early L-cysteine supplementation as clinically actionable interventions.

References

• Journal of medical genetics • 2011 • Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. PMID:21931168
• Human molecular genetics • 2013 • Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency. PMID:23814040

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