Alternative titles; symbols
HGNC Approved Gene Symbol: HARS2
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38) : 5:140,691,455-140,699,305 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | Perrault syndrome 2 | 614926 | Autosomal recessive | 3 |
The HARS2 gene encodes a histidyl tRNA synthetase, a highly conserved protein that functions in mitochondria (summary by Pierce et al., 2011).
O'Hanlon et al. (1995) identified the HARS2 gene, which they called HO3, oriented head-to-head with the HARS gene (142810). The deduced 506-amino acid HO3 protein has a calculated molecular mass of 56.9 kD. HO3 shares 72% amino acid identity with HARS. Both proteins contain 3 motifs conserved among class II aminoacyl-tRNA synthetases and 2 signature regions of histidyl-tRNA synthetases. However, HARS and HARS2 have divergent N-terminal domains that are encoded by the first 2 exons of each gene. Northern blot analysis detected a 2.5-kb HO3 transcript that was highly expressed in heart, skeletal muscle, and kidney, with lower expression in brain and liver.
Using 5-prime RACE with a human kidney cDNA library, O'Hanlon and Miller (2002) identified several HARSL transcripts that differed only in the lengths of their 5-prime UTRs. They also identified HARSL transcripts containing an alternatively spliced 91-bp exon within their 5-prime UTRs. O'Hanlon and Miller (2002) reported that the mouse and human HARSL proteins share 83.9% amino acid identity. They noted that the HARSL protein lacks 60 N-terminal amino acids found in HARS that are necessary for enzymatic activity, suggesting that HARSL may not function as a tRNA synthetase.
By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified HARS2, which they called mitochondrial HISRS. The deduced 506-amino acid protein has an N-terminal mitochondrial targeting signal with a predicted cleavage site after residue 34. HARS2 has characteristics of a class II mitochondrial aminoacyl-tRNA synthetase and is expected to function as a dimer.
Pierce et al. (2011) found high expression of the HARS2 gene in the mitochondria of mammalian cells.
O'Hanlon and Miller (2002) determined that the HARS2 gene contains 13 exons and spans about 7.9 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites.
Bonnefond et al. (2005) reported that the HARS2 gene contains 13 exons and spans 6.9 kb.
By genomic sequence analysis, O'Hanlon et al. (1995) mapped the HARS2 gene to chromosome 5, where it is oriented head-to-head with the HARS gene.
O'Hanlon and Miller (2002) mapped the HARS and HARS2 genes to chromosome 5q31.3 by genomic sequence analysis. The ORFs of HARS and HARS2 are separated by 344 bp.
In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene (600783.0001 and 600783.0002). The mutations, which were found by linkage analysis followed by candidate gene sequencing, were shown to cause decreased enzyme activity. Affected females had sensorineural deafness, primary amenorrhea, streak gonads, and infertility, whereas affected males had deafness, normal pubertal development, and were fertile.
Zou et al. (2020) identified compound heterozygous mutations in the HARS gene (R191Q, 600783.0003 and R208C, 600783.0004) in a Han Chinese patient (D2092) with isolated severe to profound sensorineural hearing loss. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.
Pierce et al. (2011) demonstrated that 50% knockdown of the Hars1 gene in C. elegans resulted in severe gonadal defects, including smaller, narrower gonads and absence of oocytes or fertilized eggs in the majority of animals. The animals were almost completely sterile. The loss of fertility apparently resulted from increased apoptosis of germ cells. Complete knockdown of the Hars1 gene resulted in arrested development at the L2 larvae stage.
In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene: a paternally inherited 598C-G transversion in exon 6 resulting in a leu200-to-val (L200V) substitution at a highly conserved residue, and a maternally inherited 1102G-T transversion in exon 10 resulting in a val368-to-leu (V368L; 600783.0002) substitution at a highly conserved residue. The mutations were found by linkage analysis followed by candidate gene sequencing. Neither mutation was found in 1,942 control individuals. Study of patient lymphoblasts showed that the 598C-G mutation also created an alternative splice site, resulting in an in-frame deletion of 12 codons in exon 6 (delta200-211). The deletion transcript was present at much lower levels in the unaffected father compared to the affected children. Both mutant missense proteins were expressed, could dimerize, and localized to the mitochondria in mammalian cells, but the deletion transcript was poorly expressed, suggesting that it is unstable. Both missense mutations had significantly decreased enzymatic activity compared to wildtype, with the V368L mutation showing a more severe effect. Modeling of the homologous mutations in yeast also indicated that the V368L mutant had a more severe effect on enzyme activity. Based on the functions of mitochondrial tRNA synthetases and cellular defects resulting from their mutation, Pierce et al. (2011) speculated that mutations in HARS2 result in decreased mitochondrial translation and respiratory chain defects in affected tissues.
For discussion of the val368-to-leu (V368L) mutation in the HARS2 gene that was found in compound heterozygous state in affected members of a family with Perrault syndrome-2 (PRLTS2; 614926) by Pierce et al. (2011), see 600783.0001.
In a Han Chinese patient (D2092) with Perrault syndrome-2 (PRLTS2; 614926) with isolated severe to profound sensorineural hearing loss, Zou et al. (2020) identified compound heterozygous mutations in the HARS gene: a c.572G-A transition (c.572G-A, NM_001278731), resulting in an arg191-to-gln (R191Q) substitution, and a c.622C-T transition, resulting in an arg208-to-cys (R208C; 600783.0004) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutations were shown to be in trans, with each parent confirmed to carry one mutation. The R191Q variant was not reported in the 1000 Genomes Project database; it was reported in the gnomAD database at a frequency of 0.00000797 and was identified in an internal database of 414 Han Chinese control subjects at a frequency of 0.00023652. The R208C variant was not reported in the 1000 Genomes Project database or in an internal database of 2,114 Han Chinese control subjects, but was reported in the gnomAD database at a frequency of 0.00001593. Functional studies were not performed.
For discussion of the c.622C-T transition (c.622C-T, NM_001278731) in the HARS2 gene, resulting in an arg208-to-cys (R208C) substitution, that was found in compound heterozygous state in a Han Chinese patient with Perrault syndrome-2 (PRLTS2; 614926) by Zou et al. (2020), see 600783.0003.
Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 44: 4805-4816, 2005. [PubMed: 15779907] [Full Text: https://doi.org/10.1021/bi047527z]
O'Hanlon, T. P., Miller, F. W. Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL). Biochem. Biophys. Res. Commun. 294: 609-614, 2002. [PubMed: 12056811] [Full Text: https://doi.org/10.1016/S0006-291X(02)00525-9]
O'Hanlon, T. P., Raben, N., Miller, F. W. A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS. Biochem. Biophys. Res. Commun. 210: 556-566, 1995. [PubMed: 7755634] [Full Text: https://doi.org/10.1006/bbrc.1995.1696]
Pallister, P. D., Opitz, J. M. The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness. Am. J. Med. Genet. 4: 239-246, 1979. [PubMed: 517579] [Full Text: https://doi.org/10.1002/ajmg.1320040306]
Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc. Nat. Acad. Sci. 108: 6543-6548, 2011. [PubMed: 21464306] [Full Text: https://doi.org/10.1073/pnas.1103471108]
Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H. Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients. Clin. Genet. 97: 352-356, 2020. [PubMed: 31486067] [Full Text: https://doi.org/10.1111/cge.13638]