NARS2 – Combined oxidative phosphorylation deficiency 24

NARS2 encodes the mitochondrial asparaginyl-tRNA synthetase, essential for charging mt-tRNA^Asn and enabling efficient mitochondrial protein synthesis. Biallelic variants in NARS2 are causative for autosomal recessive Combined oxidative phosphorylation deficiency 24 (COXPD24), characterized by early-onset epilepsy, sensorineural hearing loss, growth retardation and multisystem involvement.

COXPD24 follows an autosomal recessive inheritance pattern with six probands described across four unrelated families ([PMID:35558980]; [PMID:34374940]; [PMID:38310242]; [PMID:36620461]). One sib-pair from a consanguineous family confirmed homozygous segregation of c.545T>A (p.Ile182Lys) in both affected sisters ([PMID:34374940]), supporting familial segregation.

Case reports have detailed compound heterozygous and homozygous missense and splice-site variants. Notably, c.1141A>G (p.Asn381Asp) impairs NARS2 expression and phenocopies COXPD24 with generalized myoclonic seizures, deafness and cardiomyopathy ([PMID:35558980]). A single patient with c.707T>C (p.Phe236Ser) and c.1352G>A (p.Arg451His) presented refractory status epilepticus, global developmental delay and myocardial dysfunction ([PMID:38310242]).

Two unrelated infants with epilepsia partialis continua, hearing loss and growth delay harbored c.185T>C (p.Leu62Pro) and c.509T>G (p.Phe170Cys) in trans with the donor-site variant c.251+2T>G. Minigene experiments confirmed aberrant splicing leading to truncated products and molecular dynamics highlighted impaired dimer stability ([PMID:36620461]).

Functional studies demonstrate multiple pathogenic mechanisms. The c.251+2T>G splice-site variant produces variable exon skipping in minigene assays ([PMID:36620461]). Missense alleles such as p.Asn381Asp and p.Phe236Ser reduce steady-state NARS2 levels in HEK293T cells without affecting mitochondrial localization or dimer formation ([PMID:35558980]; [PMID:38310242]). Patient fibroblasts show combined complex I/IV deficiency, decreased mt-tRNA^Asn aminoacylation and diminished oxygen consumption.

Collectively, genetic and experimental data across six probands and one sib-pair establish a strong gene–disease relationship. The variant spectrum includes missense (n = 5) and splice-site (n = 1) alleles, all confirmed by segregation and functional assays. This evidence supports AR NARS2 testing in infants with unexplained early-onset epilepsy, hearing impairment and growth failure.

Key Take-home: NARS2 should be prioritized in autosomal recessive mitochondrial encephalopathies presenting with epilepsy and sensorineural hearing loss.

References

• Translational Pediatrics • 2022 • Study of novel NARS2 variants in patient of combined oxidative phosphorylation deficiency 24. PMID:35558980
• Irish Journal of Medical Science • 2022 • Novel phenotype and genotype spectrum of NARS2 and literature review of previous mutations. PMID:34374940
• BMC Pediatrics • 2024 • Novel NARS2 variants in a patient with early-onset status epilepticus: case study and literature review. PMID:38310242
• Frontiers in Neuroscience • 2022 • Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations. PMID:36620461

Evidence Based Scoring (AI generated)