Several components of mtDNA replication, transcription, and translation processes, including tRNA maturation, initiation and elongation factors, ribosomal proteins, and aminoacyl-tRNA synthetases (mt-aaRSs), are encoded by nuclearDNA (nDNA), synthed in the cytosol and imported into the mitochondria. nDNA-encoded mt-aaRS genes produce enzymes that play an important role in protein synthesis by charging tRNAs with their cognate amino acid and ensuring correct protein translation. Pathogenic variants in mt-aaRSs can directly affect the central nervous system, leading to characteristic brain lesion patterns (e.g. leukodystrophies) that can be identified by magnetic resonance imaging (MRI).
The nuclear gene EARS2 encodes glutamyl-tRNA synthetase, a member of the class I family of mt-aaRSs. This 523-amino acid protein has an N-terminal mitochondrial targeting signal that enables its importation from the cytoplasm into the mitochondria, where it catalyzes the acylation of tRNAGln with glutamine. Genetic defects in EARS2 may lead to combined OXPHOS deficiency, an autosomal recessive neurologic disorder caused by either compound heterozygous or homozygous variants. The EARS2 gene mutations involved in LTBL likely reduce the amount of mitochondrial glutamyl-tRNA synthetase. A shortage of this protein is thought to prevent the normal assembly of new proteins within mitochondria and this can impair protein assembly which disrupts mitochondrial energy production.
It has been difficult to establish a correlation between patients genotypic and phenotypic characteristics, since the same variant may be associated with diļ¬erent clinical signs, even among members of the same family.
EARS2