NARS2 – Mitochondrial Disease

NARS2 encodes the mitochondrial asparaginyl-tRNA synthetase, essential for charging mt-tRNAAsn during oxidative phosphorylation. Biallelic NARS2 variants underlie a spectrum of mitochondrial disorders, including Leigh syndrome and sensorineural hearing loss, through combined complex I and IV deficiencies in patient tissues ([PMID:25807530]).

Inheritance is autosomal recessive with both homozygous and compound heterozygous missense, splice-site, and truncating alleles reported in over 15 probands from multiple unrelated families ([PMID:25807530], [PMID:36252909]). Segregation analyses in affected sibships and families confirm co-segregation of NARS2 variants with disease phenotypes ([PMID:25385316], [PMID:36252909]).

Genetic screening of pediatric cohorts via dual genomic sequencing identified NARS2 among nuclear DNA mitochondrial disease genes in patients meeting clinical mitochondrial criteria ([PMID:36918699]). Yeast complementation assays of human NARS2 variants demonstrated impaired oxidative growth, reduced oxygen consumption, and decreased Cox2 levels, leading to reclassification of several variants as likely pathogenic ([PMID:39230874]).

Functional studies in patient fibroblasts and muscle show exon-skipping and decreased charged mt-tRNAAsn for splice-site alleles, reduced NARS2 protein stability for missense and truncating mutations, and rescue of respiratory chain defects by wild-type NARS2 overexpression ([PMID:25385316]). These data support a loss-of-function mechanism causing mitochondrial translation failure and OXPHOS deficiency.

Conflicting evidence is limited, with no reported healthy individuals homozygous or compound heterozygous for pathogenic NARS2 alleles, and in silico models consistently predict deleterious effects on protein structure and dimerization ([PMID:36252909]).

Overall, the genetic and experimental concordance for NARS2 in mitochondrial disease reaches a Strong clinical validity. NARS2 variant testing informs diagnosis, family counseling, and potential therapeutic strategies such as amino acid supplementation.

Key Take-home: Biallelic loss-of-function NARS2 variants cause autosomal recessive mitochondrial disease via impaired mt-tRNA charging and OXPHOS deficiency, supporting their use in clinical genetic diagnosis.

References

• PLoS genetics • 2015 • Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PMID:25807530
• European journal of medical genetics • 2022 • Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability. PMID:36252909
• Human mutation • 2015 • Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). PMID:25385316
• Scientific reports • 2023 • Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis. PMID:36918699
• Human molecular genetics • 2024 • Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases. PMID:39230874

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