NARS2 – Leigh Syndrome

Leigh syndrome is a progressive neurodegenerative mitochondrial disorder characterized by symmetric bilateral lesions in the basal ganglia and brainstem. Biallelic variants in NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, have been implicated in autosomal recessive Leigh syndrome, expanding the genetic heterogeneity of this condition.

Genetic evidence supports an autosomal recessive inheritance mode with at least three unrelated probands reported. A compound heterozygous pair c.969T>G (p.Tyr323Ter) and c.1142A>G (p.Asn381Ser) was identified in one family presenting with respiratory chain deficiency and classic Leigh neuropathology ([PMID:25807530]). A second unrelated patient harbored c.731C>G (p.Ala244Gly) and c.556A>G (p.Asn186Asp) with normal lactate levels at presentation but classic MRI changes ([PMID:35508527]). A third individual carried c.1253G>A (p.Arg418His) and c.1300C>T (p.Leu434Phe) alongside SDHA and ECHS1 variants in a tri-genic analysis of Leigh syndrome pedigrees ([PMID:35014173]).

The variant spectrum spans missense substitutions affecting conserved residues and predicted loss-of-function alleles introducing premature termination codons. Recurrent LoF alleles such as c.969T>G (p.Tyr323Ter) have been observed across populations, suggesting a critical requirement for full-length NARS2 in mitochondrial translation.

Segregation analysis in all three families demonstrated parental carrier status and absence of disease in heterozygotes, confirming recessive transmission. No additional affected relatives were reported beyond index cases and sibling pairs.

Functional assays have demonstrated the pathogenic mechanism of NARS2 variants. In patient fibroblasts, p.Tyr323Ter abrogates detectable NARS2 protein, while p.Asn381Ser reduces steady-state levels and disrupts homodimer formation, leading to decreased mt-tRNAAsn charging, reduced oxygen consumption rates, and impaired electron transport chain activity. Overexpression of wild-type NARS2, but not the p.Val213Phe hearing loss mutant, rescues these defects, confirming loss of function as the disease mechanism ([PMID:25807530]).

Yeast complementation studies further corroborate variant pathogenicity: expression of human NARS2 missense alleles in msr1∆ yeast strains recapitulates oxidative growth defects and reduced Cox2 levels, which are partially ameliorated by amino acid supplementation, highlighting potential therapeutic avenues ([PMID:39230874]).

Collectively, genetic and functional data establish a moderate level of clinical validity for NARS2 in Leigh syndrome. Biallelic pathogenic variants are consistently associated with mitochondrial translation defects and Leigh neuropathology. Routine inclusion of NARS2 in diagnostic gene panels and functional confirmation of novel variants enhance diagnostic yield and enable accurate genetic counseling.

Key Take-home: NARS2 loss-of-function causes autosomal recessive Leigh syndrome via defective mt-tRNAAsn charging; genetic testing is essential for diagnosis and clinical management.

References

• PLoS genetics • 2015 • Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome PMID:25807530
• Human genome variation • 2022 • Novel NARS2 variant causing leigh syndrome with normal lactate levels. PMID:35508527
• American journal of medical genetics. Part A • 2022 • Whole-exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees. PMID:35014173
• 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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