RARS2 – Mitochondrial Disease

Biallelic variants in the nuclear‐encoded mitochondrial arginyl‐transfer RNA synthetase gene RARS2 underlie a spectrum of early‐onset mitochondrial disorders, most notably pontocerebellar hypoplasia type 6, but also more broadly manifesting as multisystem mitochondrial disease (Mitochondrial Disease).

RARS2 defects follow an autosomal recessive inheritance pattern. To date, at least eight unrelated probands in four families have been reported with biallelic RARS2 variants. These include two siblings homozygous for a non‐coding promoter change c.-2A>G (PMID:25809939) and a patient compound heterozygous for a frameshift c.633_636del (p.Glu212fsTer) and an intronic allele (PMID:32071833). Three additional pedigrees harbor diverse missense and truncating mutations identified by exome or panel sequencing (PMID:35468344; PMID:37344844).

The variant spectrum comprises five missense changes, two predicted loss‐of‐function alleles (frameshift and nonsense), and one Kozak/promoter variant. Recurrent frameshifting and promoter mutations have been observed in multiple ancestries. Population frequencies are negligible, consistent with recessive pathogenicity.

Segregation data confirm autosomal recessive transmission, including one instance of affected siblings carrying the c.-2A>G variant in homozygosity (PMID:25809939). No healthy adults with biallelic pathogenic alleles have been reported.

Multiple functional assays corroborate pathogenicity. Knockdown of the yeast RARS2 orthologue MSR1 expressing patient alleles impairs oxidative growth, reduces Cox2 levels, and limits mitochondrial protein synthesis, leading to reclassification of most variants as likely pathogenic (PMID:39230874). Zebrafish rars2 depletion phenocopies pontocerebellar hypoplasia and is partially rescued by human RARS2 mRNA, supporting a loss‐of‐function mechanism (PMID:21273289). A Kozak‐sequence promoter variant (c.-2A>G) markedly decreases RARS2 protein translation in patient fibroblasts (PMID:37344844), and human neuronal progenitor models reveal gene‐specific integrated stress response activation in RARS2‐deficient cells (PMID:37975900).

No contradictory evidence disputing the association has been reported. Altogether, the genetic and experimental data support a loss‐of‐function mechanism for RARS2 in mitochondrial disease. Further large‐scale studies may refine genotype–phenotype correlations.

Key take‐home: Biallelic RARS2 variants cause autosomal recessive mitochondrial disease via impaired mitochondrial protein translation; functional assays and segregation strongly support pathogenicity and guide molecular diagnosis.

References

• 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
• Scientific reports • 2023 • Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis. PMID:36918699
• Journal of human genetics • 2015 • A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. PMID:25809939
• Human molecular genetics • 2011 • Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia. PMID:21273289
• JIMD reports • 2020 • Phenotypes and genotypes of mitochondrial aminoacyl-tRNA synthetase deficiencies from a single neurometabolic clinic. PMID:32071833
• Pediatric neurology • 2022 • Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6. PMID:35468344
• BMC medical genomics • 2023 • A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia. PMID:37344844
• Human molecular genetics • 2024 • Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons. PMID:37975900

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