HARS2 encodes mitochondrial histidyl-tRNA synthetase, which is crucial for linking histidine to its cognate tRNA in the mitochondrial matrix. This process is essential for mitochondrial protein synthesis, thus influencing mitochondrial function, a key aspect in various biological processes [1].

Biallelic variants in HARS2 are associated with Perrault syndrome, characterized by sensorineural hearing impairment and primary ovarian insufficiency in females. In a study, targeted knockout of Hars2 in mouse cochlear hair cells led to progressive hearing loss, resembling the Perrault syndrome hearing phenotype. It caused mitochondrial dysfunction, increased reactive oxygen species, and activated the mitochondrial apoptotic pathway, resulting in hair cell loss and synaptic exocytosis compromise [2].

In summary, HARS2 is vital for mitochondrial protein synthesis through its role as a histidyl-tRNA synthetase. The Hars2 knockout mouse model has been instrumental in revealing its role in sensorineural hearing loss and conditions like Perrault syndrome, highlighting its significance in understanding these disease mechanisms [2].

References:

1. Demain, Leigh A M, Gerkes, Erica H, Smith, Richard J H, O'Keefe, Raymond T, Newman, William G. 2019. A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families. In Journal of human genetics, 65, 305-311. doi:10.1038/s10038-019-0706-1. https://pubmed.ncbi.nlm.nih.gov/31827252/

2. Xu, Pengcheng, Wang, Longhao, Peng, Hu, Wu, Hao, Yang, Tao. 2021. Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice. In Frontiers in cellular neuroscience, 15, 804345. doi:10.3389/fncel.2021.804345. https://pubmed.ncbi.nlm.nih.gov/34975414/