Prolyl-tRNA synthetase 2, mitochondrial (PARS2)

Prolyl-tRNA synthetase 2, mitochondrial (PARS2), is a nuclear-encoded, mitochondrial-localized class II aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of proline to mitochondrial tRNA(Pro), a reaction essential for mitochondrial protein translation and thus for the function of the oxidative phosphorylation system. Mutations in PARS2 disrupt mitochondrial protein synthesis and are associated with severe multisystem disorders, most notably developmental and epileptic encephalopathy 75 (DEE75), Alpers syndrome, and various forms of mitochondrial cardiomyopathy. Clinical manifestations commonly include seizures, developmental delay, hypotonia, microcephaly, cardiomyopathy, and lactic acidemia; MRI and laboratory findings support mitochondrial dysfunction. To date, no direct drugs or therapies target PARS2, and management relies on supportive care. Pathogenic missense or truncating variants of PARS2 result in enzyme deficiency and impaired mitochondrial translation, underlining its essential role in health; disease prognosis is typically poor, with young age at death in most reported cases.

Other names

ProRSProlyl-tRNA synthetase 2, mitochondrialProlyl-tRNA synthetaseProline tRNA ligase 2, mitochondrial (putative)Probable proline--tRNA ligase, mitochondrialDKFZp727A071DEE75 / EIEE75 (disease association: developmental and epileptic encephalopathy 75)MT-PRORSproRS

No direct drugs targeting PARS2 are known. For supportive therapies, their mechanisms include supporting mitochondrial function (e.g., antioxidants, cofactors), providing antiepileptic action (e.g., ACTH, antiepileptics for seizure control), and managing cardiac failure (e.g., standard drugs for heart failure). These treatments do not directly target PARS2 but manage symptoms arising from its deficiency.