Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome

Defects in nuclear-encoded proteins of themitochondrial translationmachinery cause early-onset and tissue-specific deficiency of one ormore OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreasedmtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive ofmitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the commonm.3243A > Gmutation was excluded. Targeted exome sequencing of genes encoding themitochondrial proteome identified a damagingmutation, c.567G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a human disease and encodes an enzyme responsible for 2'-O-methylmodification at position U1369 in the humanmitochondrial 16S rRNA.We generated a knockout yeastmodel for the orthologous gene that showed a defect in respiration and the reduction of the 2'-O-methylmodification at the equivalent position (U2791) in the yeastmitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeastmutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with am.3243A > G negative MELAS-like presentation.