|Gene (OMIM no.)|
|Function of gene/protein|
|Clinical phenotype (with OMIM phenotype no.)|
Usher syndrome 3B
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
Mutations in HARS1 were identified in three Old Order Amish patients with a homozygous missense mutation, c.1361A>C, p.(Tyr454Ser), who were diagnosed with Usher syndrome type 3B.1 In addition to progressive hearing and visual loss from childhood, patients showed motor impairment. Subsequently, several studies have found monoallelic mutations in HARS1 associated with autosomal dominant Charcot–Marie–Tooth disease, a motor and sensory peripheral neuropathy affecting both lower and upper limbs.2–5 Biallelic HARS1 mutations have also been identified in three patients with multisystem ataxic syndrome.6
- Puffenberger EG, Jinks RN, Sougnez C, et al. Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases. PLoS One. 2012;7(1).
- Vester A, Velez-Ruiz G, McLaughlin HM, et al. A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. Hum Mutat. 2013;34(1):191-199.
- Safka Brozkova D, Deconinck T, Griffin LB, et al. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain. 2015;138(Pt 8):2161-2172.
- Abbott JA, Meyer-Schuman R, Lupo V, et al. Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Hum Mutat. 2018;39(3):415-432.
- Royer-Bertrand B, Tsouni P, Mullen P, et al. Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant. Ann Clin Transl Neurol. 2019;6(6):1072-1080.
- Galatolo D, Kuo ME, Mullen P, et al. Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome. Hum Mutat. 2020;41(7):1232-1237.