SSIEM 2014 Annual Symposium: Abstracts

We report a pathogenic mutation in NARS2, a gene coding for an asparaginyl tRNA synthetase, previously not associated with a disease. The two reported siblings were from consanguineous origin and presented with myopathy and mild mental retardation. Using homozygosity mapping we found two candidate genes and detected a pathogenic homozygous mutation (c.822G>C; p. Q274H) by conventional dideoxysequencing in NARS2. In both siblings, a combined OXPHOS deficiency involving complex I and IV was detected in skeletal muscle. Additional analysis by BN-PAGE followed by in-gel activity staining confirmed these findings and revealed the presence of complex V subcomplexes, the hallmark of defective intramitochondrial protein synthesis. The pathogenic character of the mutation was demonstrated by northern blotting experiments. The findings in these siblings add a new aminoacid tRNA synthetase (aaRS) to the list of nuclear defects causing OXPHOS deficiency and increase the likelihood that ultimately all mitochondrial aaRS will be associated with clinical phenotypes. During the last decade, an increasing number of new molecular defects residing within the nuclear genome have been recognized causing OXPHOS deficiencies.Most of these genes encode proteins related to mtDNA transcription or translation. A particular subgroup encodes the mitochondrial aaRS, responsible for linking the correct amino acid to its corresponding tRNA.