HARS1 gene

• Overview
• Usher syndrome
• Retinitis pigmentosa
• Additional information
• References

Overview

Gene (OMIM no.)	HARS1 (#142810)
Function of gene/protein	Aminoacyl‐tRNA synthetase Charges tRNA with the amino acid histidine in the cytoplasm as the first step in protein translation
Clinical phenotype (with OMIM phenotype no.)	Usher syndrome type 3B (#614504) Charcot-Marie-Tooth disease, axonal, type 2W (#616625)
Inheritance	Autosomal recessive (Usher syndrome) Autosomal dominant (Charcot-Marie-Tooth disease)
Ocular features	Retinitis pigmentosa Fine horizontal nystagmus Light aversion
Visual function	Nyctalopia and peripheral visual field loss by second decade of life Loss of central and colour vision in later life
Systemic features	Usher syndrome 3B Congenital bilateral sensorineural hearing loss from infancy Delayed gross motor development Mild truncal ataxia and wide-based gait Normal peripheral nerve function Charcot-Marie-Tooth disease Progressive peripheral neuropathy (motor and sensory) Variable severity and onset Foot deformities Gait difficulties
Key investigations	Pure tone audiometry Electrophysiology Fundus autofluorescence (FAF): a ring of hyper-AF in the macula Optical coherence tomography (OCT): progressive loss of outer retinal structures which spares the fovea initially; cystoid macular oedema may be detected Kinetic perimetry Nerve conduction studies if Charcot-Marie-Tooth disease is suspected
Molecular diagnosis	Next generation sequencing Targeted gene panels (retinal and deafness) Whole exome sequencing Whole genome sequencing Targeted exome sequencing
Management	Neurologic assessment Developmental clinic assessment with multidisciplinary input Hearing aids/cochlear implants Management of retinitis pigmentosa Management of Usher syndrome
Therapies under research	None in clinical trials
Further information	Genecards.org

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Additional Information

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

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References

1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.

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