Alternative titles; symbols
HGNC Approved Gene Symbol: HARS1
SNOMEDCT: 1172634009;
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:140,673,905-140,691,370 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | Charcot-Marie-Tooth disease, axonal, type 2W | 616625 | Autosomal dominant | 3 |
| Usher syndrome type 3B | 614504 | Autosomal recessive | 3 |
HARS catalyzes the covalent ligation of histidine to its cognate tRNA as an early step in protein biosynthesis (O'Hanlon and Miller, 2002).
O'Hanlon et al. (1995) noted that HARS and HARS2 (600783), which they called HO3, are oriented in a head-to-head configuration and share a bidirectional promoter. They reported that the deduced 509-amino acid HARS protein shares 72% amino acid identity with HARS2. 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. HARS has a calculated molecular mass of 57.4 kD. Northern blot analysis detected a 2.0-kb HARS transcript that was highly expressed in heart, brain, liver, and kidney.
Using 5-prime RACE with a human kidney cDNA library, O'Hanlon and Miller (2002) identified several HARS transcripts that differed only in the lengths of their 5-prime UTRs. O'Hanlon and Miller (2002) noted that pufferfish and human HARS proteins share 84% amino acid homology, suggesting a high degree of conservation.
Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 8 catalytic-null splice variants for HisRS.
O'Hanlon and Miller (2002) determined that the HARS gene contains 13 exons and spans approximately 17.4 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites. HARS also uses a second, more distal promoter that overlaps the first exons of the HARS2 gene.
Carlock et al. (1985) used a Chinese hamster ovary (CHO) cell line with mutations in 3 genes, HARS, RPS14 (130620) and CHR (118840), in interspecies cell hybridization experiments, to assign the HARS gene to chromosome 5. Wasmuth and Carlock (1986) assigned the HARS gene to chromosome 5 by use of human-Chinese hamster ovary cell hybrids.
By genomic sequence analysis, O'Hanlon and Miller (2002) mapped the HARS and HARS2 genes to chromosome 5q31.3. HARS and HARS2 exhibit a head-to-head orientation, with 344 bp separating their ORFs.
Usher Syndrome Type III
In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type III mapping to chromosome 5q (USH3B; 614504), Puffenberger et al. (2012) identified homozygosity for a missense mutation in the HARS gene (Y454S; 142810.0001) that was not found in dbSNP 129 or the 1000 Genomes Project. In addition, an Old Order Amish patient from an unrelated deme in Ontario, Canada, had an identical phenotype and was homozygous for the same mutation.
Charcot-Marie-Tooth Disease Type 2W
In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Vester et al. (2013) identified a heterozygous missense mutation in the HARS gene (R137Q; 142810.0002). The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects.
In affected members of 4 unrelated families with CMT2W, Safka Brozkova et al. (2015) identified 4 different heterozygous missense mutations in the HARS gene (142810.0003-142810.0006). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. All mutations caused a loss of function in yeast complementation assays, and 1 of the mutations was dominantly neurotoxic in a C. elegans model.
In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type IIIB (USH3B; 614504), Puffenberger et al. (2012) identified homozygosity for a 1361A-C transversion in the HARS gene, resulting in a tyr454-to-ser (Y454S) substitution in the interface between the catalytic domain and the anticodon binding domain. A patient with an identical phenotype from an unrelated Old Order Amish deme in Ontario, Canada, was also homozygous for the Y454S mutation. The variant was not found in the dbSNP (build 129) or the 1000 Genomes Project databases; however, it was detected in 7 of 406 Old Order Amish alleles, for a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)
In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Vester et al. (2013) identified a heterozygous 410G-A transition (rs191391414) in the HARS gene, resulting in an arg137-to-gln (R137Q) substitution at a highly conserved residue in the catalytic core of the enzyme. The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. The R137Q variant was also found in 3 of over 13,000 control chromosomes. One of the control carriers had no evidence of neuropathy at age 57 years. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. Vester et al. (2013) concluded that the HARS R137Q variant may be a pathogenic allele that predisposes to the development of peripheral neuropathy, similar to other ARS mutations (see, e.g., GARS, 600287), but noted that a causal link remains unclear.
In affected members of a large multigenerational family (family A) with Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.395C-T transition in the HARS gene, resulting in a thr132-to-ile (T132I) substitution. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function.
In affected members of a family (family B) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.401C-A transversion in the HARS gene, resulting in a pro134-to-his (P134H) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function.
In affected members of a 3-generation family (family C) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.525T-G transversion in the HARS gene, resulting in an asp175-to-glu (D175E) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was only partially able to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a partial loss of function.
In affected members of a multigenerational family (family D) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.1090G-T transversion in the HARS gene, resulting in an asp364-to-tyr (D364Y) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. Expression of the D364Y mutation in C. elegans resulted in morphologic neurotoxicity, including dorsal and ventral nerve gaps, axonal blebbing, and severely aberrant axonal processes. Animals with the mutation also showed progressively impaired locomotor performance.
Carlock, L. R., Skarecky, D., Dana, S. L., Wasmuth, J. J. Deletion mapping of human chromosome 5 using chromosome-specific DNA probes. Am. J. Hum. Genet. 37: 839-852, 1985. [PubMed: 2996334]
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. Human tRNA synthetase catalytic nulls with diverse functions. Science 345: 328-332, 2014. [PubMed: 25035493] [Full Text: https://doi.org/10.1126/science.1252943]
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]
Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One 7: e28936, 2012. Note: Electronic Article. [PubMed: 22279524] [Full Text: https://doi.org/10.1371/journal.pone.0028936]
Puffenberger, E. G. Personal Communication. Strasburg, Pa. 2/28/2012.
Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain 138: 2161-2172, 2015. [PubMed: 26072516] [Full Text: https://doi.org/10.1093/brain/awv158]
Tsui, F. W. L., Andrulis, I. L., Murialdo, H., Siminovitch, L. Amplification of the gene for histidyl-tRNA synthetase in histidinol-resistant Chinese hamster ovary cells. Molec. Cell. Biol. 5: 2381-2388, 1985. [PubMed: 2874482] [Full Text: https://doi.org/10.1128/mcb.5.9.2381-2388.1985]
Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A. A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. Hum. Mutat. 34: 191-199, 2013. [PubMed: 22930593] [Full Text: https://doi.org/10.1002/humu.22210]
Wasmuth, J. J., Carlock, L. R. Chromosomal localization of human gene for histidyl-tRNA synthetase: clustering of genes encoding aminoacyl-tRNA synthetases on human chromosome 5. Somat. Cell Molec. Genet. 12: 513-517, 1986. [PubMed: 3464104] [Full Text: https://doi.org/10.1007/BF01539922]