CARS2 – Mitochondrial Disease

CARS2 encodes the mitochondrial cysteinyl-tRNA synthetase, essential for mitochondrial translation. Biallelic variants in CARS2 have been described in individuals with early-onset mitochondrial disease, characterized by epileptic encephalopathy, movement disorders, and combined respiratory chain deficiencies. The overall clinical validity is assessed as Moderate based on multiple probands, segregation data, and concordant functional studies.

In 2015, a single proband presented with intractable seizures, a complex movement disorder, and progressive developmental regression, alongside combined deficiencies of mitochondrial complexes I, III, IV, and V in liver and muscle tissue. Compound heterozygous CARS2 variants—c.752C>T (p.Pro251Leu) and c.649_651del (p.Glu217del)—were identified by exome sequencing, and complementation in patient fibroblasts corrected complex V assembly ([PMID:25787132]).

A retrospective cohort of 101 pediatric patients with suspected mitochondrial disorders from China identified a CARS2 variant in an affected individual, contributing to the gene’s mutation spectrum in mitochondrial disease ([PMID:32348839]). This supports a recurrent autosomal recessive inheritance pattern and underscores a broader CARS2-associated phenotypic range.

In a consanguineous family with two affected siblings resembling MERRF syndrome, a homozygous splice-site variant, c.655G>A (p.Ala219Thr), led to exon 6 skipping and an in-frame 28–amino acid deletion in the functional ligase domain. Cosegregation analysis confirmed autosomal recessive transmission, and mRNA analysis demonstrated aberrant splicing ([PMID:25361775]).

Functional assays across studies demonstrate that pathogenic CARS2 variants reduce charged mt-tRNA(Cys) levels, impair mitochondrial translation, and disrupt respiratory chain assembly. Retroviral transfection of wild-type CARS2 in patient fibroblasts rescues complex V assembly, establishing a loss-of-function mechanism.

In summary, biallelic CARS2 variants cause a mitochondrial translational defect leading to epileptic encephalopathy and movement disorders. Genetic testing of CARS2 in autosomal recessive mitochondrial disease presentations is clinically indicated, with functional assays available for variant interpretation.

References

• Journal of medical genetics • 2015 • Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. PMID:25787132
• European journal of medical genetics • 2020 • Clinical and molecular characterization of pediatric mitochondrial disorders in south of China. PMID:32348839
• Neurology • 2014 • A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy. PMID:25361775

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