期刊
HUMAN MUTATION
卷 36, 期 2, 页码 222-231出版社
WILEY
DOI: 10.1002/humu.22728
关键词
NARS2; mitochondria; mitochondrial aminoacyl-tRNA synthetase; combined oxidative phosphorylation deficiency
资金
- FWO (Fonds voor Wetenschappelijk Onderzoek) [G.0666.06]
- Special Research Fund (BOF) from the Ghent University [B/00559/0]
- Medical Research Council, UK [MC_U105697135]
- MRC [MC_U105697135] Funding Source: UKRI
- Medical Research Council [MC_U105697135] Funding Source: researchfish
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.
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