Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome

Abstract

Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encepha- lomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial en- cephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was ex- cluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a hu- man disease and encodes an enzyme responsible for 2’-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of the 2’-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead com- pletely 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 a m.3243 A > G negative MELAS-like presentation.European Commission under ‘Marie Skłodowska-Curie Actions’, Individual Fellowship – Reintegration Panel (Mitobiopath-705560), MRC core funding (MC_U105697135), Fundação para a Ciência e a Tecnologia, Portugal (PD/BD/105750/2014), Fondazione Telethon (Italy) (grant GGP15041), European Union Seventh Framework Programme FP7 (602531) under the project ‘DESIRE’, NRJ-Institut de France grant and ERC advanced grant FP7-322424 (MZ) and National Institutes of Health (VKM, NIH R01 GM0077465 and R35GM122455). Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council, UK