Alternative titles; symbols
HGNC Approved Gene Symbol: IARS1
Cytogenetic location: 9q22.31 Genomic coordinates (GRCh38): 9:92,210,207-92,293,697 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.31 | Growth retardation, impaired intellectual development, hypotonia, and hepatopathy | 617093 | Autosomal recessive | 3 |
The autoimmune diseases polymyositis and dermatomyositis are a consequence of autoantibodies directed against 1 or more of the aminoacyl-tRNA synthetases with subsequent lymphocytic destruction of myocytes. Nichols et al. (1995) cloned the cDNA for isoleucyl-tRNA synthetase (IARS, which they referred to as IRS) by using autoantibodies from patients to purify the protein. Partial amino acid sequence was obtained from tryptic peptides and DNA probes were designed and used to screen liver and HeLa cell libraries. The cDNA encodes a predicted 1,262-amino acid protein with significant sequence similarity to isoleucyl-tRNA synthetases from both yeast and Tetrahymena. The protein contains the expected motifs of class-I hydrophobic aminoacyl-tRNA synthetases and the human protein has a C-terminal domain not seen in the lower organisms. The human gene can produce 2 alternatively spliced mRNAs based on the use of a 5-prime untranslated exon. Nichols et al. (1995) speculated that the autoantibodies produced in patients may recognize an epitope in this region.
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 1 catalytic-null splice variant for IleRS.
Six of 20 human aminoacyl-tRNA synthetases have been identified as targets of autoantibodies in the autoimmune disease polymyositis/dermatomyositis: histidyl-RS (142810) on chromosome 5, threonyl-RS (187790), also on chromosome 5, alanyl-RS (601065) on chromosome 16, glycyl-RS (600287) on chromosome 7, isoleucyl-RS, and lysyl-RS (601421).
By PCR-based analysis of a human/rodent somatic cell hybrid panel, Nichols et al. (1996) assigned IARS to chromosome 9. By fluorescence in situ hybridization analysis, they regionalized the IARS gene to 9q21.
In 3 unrelated patients with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093), Kopajtich et al. (2016) identified compound heterozygous mutations in the IARS gene (600709.0001-600709.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Yeast growth studies confirmed that each patient carried one loss-of-function allele and one hypomorphic allele.
In a boy, born of unrelated Arab parents, with GRIDHH, Orenstein et al. (2017) identified compound heterozygous missense mutations in the IARS gene (600709.0007-600709.0008). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Yeast complementation studies showed that, similar to the previously reported cases, one allele caused impaired function and the other caused loss of function.
Hereditary perinatal weak calf syndrome is associated with normal gestation period but low birth weight, anemia with bone marrow dysfunction, fetoplacental dysfunction, and increased mortality prior to 3 months of age. Calves with this syndrome exhibit depression, weakness, variable body temperature, astasia, difficulty nursing, growth retardation, and increased susceptibility to infection. In Japanese Black cattle, the syndrome was frequently found as an autosomal recessive disorder in calves sired by Bull A. Using homozygosity mapping and whole-exome and Sanger sequencing, Hirano et al. (2013) identified a homozygous c.235G-C transversion in Iars, resulting in a val79-to-leu (V79L) substitution, in calves with perinatal weak calf syndrome. The homozygous mutation was not found in normal cattle. V79 is located in the catalytic core domain of Iars, and V79 and its flanking region are highly conserved in vertebrates. Examination of artificial insemination data suggested that the V79L mutation may have contributed to embryonic or fetal death during pregnancy. Compared with recombinant wildtype Iars, mutant Iars showed reduced aminoacylation activity (38.0%).
Kopajtich et al. (2016) found that iars was ubiquitously expressed in zebrafish during early embryonic development. It localized to the somites and developing brain regions after gastrulation, especially in the tectum region of the brain, pineal gland, and hindbrain. Morpholino knockdown of the iars gene in zebrafish embryos resulted in a delay in embryonic development, with embryos showing altered brain configuration and severe shortening of the posterior body axis in a concentration-dependent manner. Zinc treatment did not result in a phenotypic rescue.
In an 18-year-old German boy (patient 65269) with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093), Kopajtich et al. (2016) identified compound heterozygous mutations in the IARS gene: a c.1252C-T transition in exon 13, resulting in an arg418-to-ter (R418X) substitution, and a c.3521T-A transversion in exon 32, resulting in an ile1174-to-asn (I1174N; 600709.0002) substitution at a highly conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.1252C-T variant was found 3 times in the heterozygous state in the ExAC database; the c.3521T-A mutation was not found in the ExAC database. The mutations were also filtered against the 1000 Genomes Project database and 7,000 in-house exomes. Immunoblot analysis of patient fibroblasts showed reduced levels of the IARS protein compared to controls. Expression of the truncating mutation in yeast with decreased Ils1, the homolog of IARS, was unable to rescue the growth defect, whereas the I1174N mutation partially rescued the growth defect.
For discussion of the c.3521T-A transversion in exon 32 of the IARS gene, resulting in an ile1174-to-asn (I1174N) substitution, that was found in compound heterozygous state in a patient with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093) by Kopajtich et al. (2016), see 600709.0001.
In a 19-year-old Japanese girl (patient 85880) with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093), Kopajtich et al. (2016) identified compound heterozygous mutations in the IARS gene: a c.760C-T transition in exon 9, resulting in an arg254-to-ter (R254X) substitution, and a c.1310C-T transition in exon 14, resulting in a pro437-to-leu (P437L; 600709.0004) substitution at a highly conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the ExAC database. The mutations were also filtered against the 1000 Genomes Project database and 7,000 in-house exomes. Immunoblot analysis of patient liver biopsy material showed no IARS, but levels in fibroblasts were normal. Expression of the truncating mutation in yeast with decreased Ils1, the homolog of IARS, was unable to rescue the growth defect, whereas the P437L mutation partially rescued the growth defect.
For discussion of the c.1310C-T transition in exon 14 of the IARS gene, resulting in a pro437-to-leu (P437L) substitution that was found in compound heterozygous state in a patient with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093) by Kopajtich et al. (2016), see 600709.0003.
In a 3-year-old Austrian boy (patient 83921) with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093), Kopajtich et al. (2016) identified compound heterozygous mutations in the IARS gene: a c.1109T-G transversion in exon 11, resulting in a val370-to-gly (V370G) substitution at a highly conserved residue, and a c.2974A-G transition in exon 28, resulting in an asn992-to-asp (N992D; 600709.0006) substitution at a highly conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were not found in the ExAC database. The mutations were also filtered against the 1000 Genomes Project database and 7,000 in-house exomes. Immunoblot analysis of patient liver biopsy material showed normal levels of IARS, whereas levels in fibroblasts were increased compared to control. Expression of the N992D mutation in yeast with decreased Ils1, the homolog of IARS, was unable to rescue the growth defect, whereas the V370G mutation partially rescued the growth defect.
For discussion of the c.2974A-G transition in exon 28 of the IARS gene, resulting in an asn992-to-asp (N992D) substitution, that was found in compound heterozygous state in a patient with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH; 617093) by Kopajtich et al. (2016), see 600709.0005.
In a boy, born of unrelated Arab parents, with intrauterine growth delay, liver dysfunction, and developmental delay (GRIDHH; 617093), Orenstein et al. (2017) identified compound heterozygosity for 2 mutations in the IARS gene: a c.2215C-T transition (c.2215C-T, NM_002161), resulting in an arg739-to-cys (R739C) substitution in a tRNA binding site, and a c.1667T-C transition, resulting in a phe556-to-ser (F556S; 600709.0008) substitution 4 residues upstream of a catalytic active site. The mutations were identified by whole-exome sequencing and segregated with the disorder in the family. The R739C mutation had a low mean allele frequency (2.47(-5)) in the ExAC database, whereas F556S was not present in the database. Complementation studies in yeast demonstrated that the R739C mutation caused loss of function, whereas the F556S mutation caused impaired function.
For discussion of the c.1667T-C transition (c.1667T-C, NM_002161) in the IARS gene, resulting in a phe556-to-ser (F556S) substitution, that was found in compound heterozygous state in a patient with intrauterine growth delay, liver dysfunction, and developmental delay (GRIDHH; 617093), by Orenstein et al. (2017), see 600709.0007.
Hirano, T., Kobayashi, N., Matsuhashi, T., Watanabe, D., Watanabe, T., Takasuga, A., Sugimoto, M., Sugimoto, Y. Mapping and exome sequencing identifies a mutation in the IARS gene as the cause of hereditary perinatal weak calf syndrome. PLoS One 8: e64036, 2013. Note: Electronic Article. [PubMed: 23700453] [Full Text: https://doi.org/10.1371/journal.pone.0064036]
Kopajtich, R., Murayama, K., Janecke, A. R., Haack, T. B., Breuer, M., Knisely, A. S., Harting, I., Ohashi, T., Okazaki, Y., Watanabe, D., Tokuzawa, Y., Kotzaeridou, U., and 16 others. Biallelic IARS mutations cause growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and infantile hepatopathy. Am. J. Hum. Genet. 99: 414-422, 2016. [PubMed: 27426735] [Full Text: https://doi.org/10.1016/j.ajhg.2016.05.027]
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]
Nichols, R. C., Blinder, J., Pai, S. I., Ge, Q., Targoff, I. N., Plotz, P. H., Liu, P. Assignment of two human autoantigen genes: isoleucyl-tRNA synthetase locates to 9q21 and lysyl-tRNA synthetase locates to 16q23-q24. Genomics 36: 210-213, 1996. [PubMed: 8812440] [Full Text: https://doi.org/10.1006/geno.1996.0449]
Nichols, R. C., Raben, N., Boerkoel, C. F., Plotz, P. H. Human isoleucyl-tRNA synthetase: sequence of the cDNA, alternative mRNA splicing, and the characteristics of an unusually long C-terminal extension. Gene 155: 299-304, 1995. [PubMed: 7721108] [Full Text: https://doi.org/10.1016/0378-1119(94)00634-5]
Orenstein, N., Weiss, K., Oprescu, S. N., Shapira, R., Kidron, D., Vanagaite-Basel, L., Antonellis, A., Muenke, M. Bi-allelic IARS mutations in a child with intra-uterine growth retardation, neonatal cholestasis, and mild developmental delay. Clin. Genet. 91: 913-917, 2017. [PubMed: 27891590] [Full Text: https://doi.org/10.1111/cge.12930]