Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2).

TitleTwo siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2).
Publication TypeJournal Article
Year of Publication2015
AuthorsVanlander, AV, Menten, B, Smet, J, De Meirleir, L, Sante, T, De Paepe, B, Seneca, S, Pearce, SF, Powell, CA, Vergult, S, Michotte, A, De Latter, E, Vantomme, L, Minczuk, M, Van Coster, R
JournalHum Mutat
Date Published2015 Feb
KeywordsAdult, Aspartate-tRNA Ligase, Base Sequence, Cells, Cultured, Consanguinity, DNA Mutational Analysis, Female, Genetic Association Studies, Homozygote, Humans, Male, Muscular Diseases, Mutation, Missense, Protein Biosynthesis, Protein Isoforms, RNA Splice Sites

A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl-tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In-gel activity staining after blue native-polyacrylamide gel electrophoresis confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole-exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3' splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV-transformed lymphoblasts, a specific decrease in the amount of charged mt-tRNA(Asn) was demonstrated as compared with controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease-associated aaRS2.

Alternate JournalHum. Mutat.
Citation Key10.1002/humu.22728
PubMed ID25385316
Grant ListMC_U105697135 / / Medical Research Council / United Kingdom