ClinVar

In 2 brothers, born of unrelated Caucasian parents (family LS06), with fatal combined oxidative phosphorylation deficiency-24 (COXPD24; 616239), Simon et al. (2015) identified compound heterozygous mutations in the NARS2 gene: a c.969T-A transversion (c.969T-A, NM_024678) in exon 10, resulting in a tyr323-to-ter (Y323X) substitution, and a c.1142A-G transition in exon 11, resulting in an asn381-to-ser (N381S; 612803.0004) substitution at a conserved residue. The mutations which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases. Both variants occurred in the catalytic domain. Patient fibroblasts showed decreased levels of NARS2 and decreased levels of aminoacylated mt-tRNA(Asn) compared to controls, although aminoacylation activity of NARS2 was normal. A truncated NARS2 protein was not detected, suggesting that the nonsense allele resulted in nonsense-mediated mRNA decay. In vitro functional expression studies in HEK293 cells showed that the N381S mutant protein was expressed at normal levels and localized normally to the mitochondria, but the mutation impaired homodimerization. The impaired oxygen consumption rate in patient cells was significantly rescued by expression of wildtype NARS2. The findings indicated that the NARS2 mutations impaired mitochondrial function.