HARS2 encodes a mitochondrial histidyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to its cognate tRNA through formation of an aminoacyl-adenylate intermediate, essential for mitochondrial protein synthesis 1. The enzyme functions within the mitochondrial matrix to support mitochondrial translation by aminoacylating tRNAHis 2. HARS2 deficiency causes significant mitochondrial dysfunction, including reduced aminoacylation efficiency, altered tRNA metabolism, decreased oxidative phosphorylation complex activities, reduced ATP levels and membrane potential, and increased reactive oxygen species production 2. Pathogenic variants in HARS2 cause Perrault syndrome 2, characterized by bilateral sensorineural hearing loss and ovarian dysgenesis 13. The syndrome results from compound heterozygous mutations that reduce HARS2 aminoacylation activity, with affected individuals showing early-onset hearing impairment and primary ovarian insufficiency 13. HARS2 is also implicated in non-syndromic hearing loss, with mutations causing prelingual, progressive hearing loss affecting middle frequencies most severely 4. The gene represents one of several mitochondrial aminoacyl-tRNA synthetases linked to primary ovarian insufficiency, highlighting the critical role of mitochondrial translation in ovarian function 56.