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 encephalomyopathy 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 encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was excluded. 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 human 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 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 a m.3243 A > G negative MELAS-like presentation.
Highlights
Mitochondria are eukaryotic intracellular organelles that play a central role in cellular metabolism by performing oxidative phosphorylation (OXPHOS) [1]
Stroke-like episodes have been recognized as a distinctive feature of maternally-inherited mitochondrial syndrome, MELAS, a multi-organ disease presenting with lactic acidemia and stroke-like episodes before age of 40 years, epilepsy, dementia and mitochondrial myopathy [35]
We report a patient presenting with encephalopathy, stroke-like episodes, lactic acidosis, hypocitrullinemia, and multiple OXPHOS defects that are all clinical, biochemical and metabolic hallmarks for a diagnosis of MELAS-like syndrome
Summary
Mitochondria are eukaryotic intracellular organelles that play a central role in cellular metabolism by performing oxidative phosphorylation (OXPHOS) [1]. Unique features of mitochondria are the presence of a 16.6 kb circular DNA molecule (mtDNA), encoding 22 tRNA, 2 rRNA and 13 protein subunits of the OXPHOS system, and intra-mitochondrial replication and translational machineries. Post-transcriptional chemical modifications of RNA, collectively referred to as epitranscriptome, are required for proper structure and function of RNA. Mitochondrial transcripts are subject to enzymatic nucleotide modifications in human mitochondria. A set of wellconserved chemical modifications to the small (12 S) and the large (16S) mitochondrial ribosomal RNAs (mt-rRNAs) has been identified and several proteins responsible for introducing these modifications have been characterized [5]. Inactivation of the mt-rRNA modifiers often result in the inhibition of mitochondrial translation and/or mitoribosome biogenesis, the exact role of these RNA modifications is largely unknown
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