Alternative titles; symbols
HGNC Approved Gene Symbol: LARS1
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:146,113,034-146,182,650 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | ?Infantile liver failure syndrome 1 | 615438 | Autosomal recessive | 3 |
The LARS gene encodes a cytoplasmic amino-acyl tRNA synthetase enzyme (aaRS) called LeuRS. LeuRS is one of several known aaRS proteins that form a macromolecular multisynthetase complex that regulates transcription, translation, and various signaling pathways (summary by Casey et al., 2012).
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 6 catalytic-null splice variants for LeuRS.
The aminoacyl-tRNA synthetases catalyze ligation of amino acids to their respective transfer RNAs. Han et al. (2012) showed that LRS senses intracellular leucine concentration and interacts directly with Rag GTPase (RRAGD; 608268). RRAGD then activates MTORC1 (601231), a key regulator of growth. When the authors modified the LRS protein to inhibit leucine binding, they observed a loss of amino acid regulation signaling to mTORC1.
Yoon et al. (2020) provided evidence for a role of LARS1 in glucose-dependent control of leucine usage. Upon glucose starvation, LARS1 was phosphorylated by UNC51-like autophagy-activating kinase-1 (ULK1; 603168) at the residues crucial for leucine binding. Phosphorylated LARS1 showed decreased leucine binding, which the authors proposed may inhibit protein synthesis and help save energy. Leucine that is not used for anabolic processes may be available for catabolic pathway energy generation. Yoon et al. (2020) concluded that the LARS1-mediated changes in leucine utilization might help support cell survival under glucose deprivation, and thus, depending on glucose availability, LARS1 may help regulate whether leucine is used for protein synthesis or energy production.
By study of hybrids of Chinese hamster and human cells, Giles et al. (1980) found evidence that a structural gene for leucyl-tRNA synthetase is on chromosome 5.
Dana and Wasmuth (1982) did cytogenetic and biochemical analyses of spontaneous segregants from Chinese hamster-human interspecific hybrid cells that contained human chromosome 5 and expressed the 4 syntenic genes LEUS, HEXB (606873), EMTB (130620), and CHR (118840), the hybrid cells being subjected to selective conditions requiring them to retain the LEUS gene. From these analyses, Dana and Wasmuth (1982) concluded that the order is as listed above and that the specific locations are: LEUS, 5pter-5q1; HEXB, 5q13; EMTB, 5q23-5q35; CHR, 5q35. Gerken et al. (1986) stated that LARS is located in 5cen-q11 and that threonyl-tRNA synthetase (187790) is closely linked, at 5p13-cen.
Following the system used for isoenzymes encoded by nuclear genes, in which 1 is used to designate the cytoplasmic or soluble form and 2 is used to designate the mitochondrial form (e.g., SOD1 (147450) and SOD2 (147460)), cytoplasmic LARS might be referred to as LARS1, and the mitochondrial form as LARS2 (604544).
In a 4-generation family of Irish Travellers segregating infantile liver failure (ILFS1; 615438), Casey et al. (2012) identified homozygosity for 2 missense mutations in the LARS gene. One (Y373C; 151350.0001) was a mutation at a conserved residue in the connective peptide-1 (CP1) domain. The other was predicted to be a rare nonpathogenic variant.
In 6 affected individuals from a consanguineous Irish Traveller family with infantile syndromic liver failure (ILFS1; 615438), Casey et al. (2012) identified homozygosity for an A-to-G transition at nucleotide 1118 (c.1118A-G) in exon 11 of the LARS gene, leading to a tyrosine-to-cysteine substitution at codon 373 (Y373C). The Y373C mutation was predicted to be highly deleterious, was highly conserved across eukaryotic species (89%), and was not present in 186 control chromosomes or in the dbSNP or 1000 Genomes Project databases. All affected individuals were also homozygous for a second mutation in cis, an A-to-G transition at nucleotide 245 in exon 4 resulting in a lysine-to-arginine substitution at codon 82 (K82R; rs112954500), which was predicted to be a rare nonpathogenic variant and was seen in 2.1% (1/48 alleles) of Irish controls but in no (0/138 alleles) Irish Travellers. All unaffected individuals of the family were either homozygous wildtype or heterozygous for the mutations. The Y373C mutation is located within the editing domain of LARS, known as connective peptide-1 (CP1), and was predicted to destabilize the protein structure. LARS knockdown achieved by siRNA in HEK293 cells had no effect on mitochondrial function even when cells were under physiologic stress.
Casey, J. P., McGettigan, P., Lynam-Lennon, N., McDermott, M., Regan, R., Conroy, J., Bourke, B., O'Sullivan, J., Crushell, E., Lynch, S., Ennis, S. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Molec. Genet. Metab. 106: 351-358, 2012. [PubMed: 22607940] [Full Text: https://doi.org/10.1016/j.ymgme.2012.04.017]
Dana, S., Wasmuth, J. J. Selective linkage disruption in human-Chinese hamster cell hybrids: deletion mapping of the leuS, hexB, emtB, and chr genes on human chromosome 5. Molec. Cell. Biol. 2: 1220-1228, 1982. [PubMed: 7177110] [Full Text: https://doi.org/10.1128/mcb.2.10.1220-1228.1982]
Gerken, S. C., Wasmuth, J. J., Arfin, S. M. Threonyl-rRNA synthetase gene maps close to leucyl-tRNA synthetase gene on human chromosome 5. Somat. Cell Molec. Genet. 12: 519-522, 1986. [PubMed: 3464105] [Full Text: https://doi.org/10.1007/BF01539923]
Giles, R. E., Shimizu, N., Nichols, E., Lawrence, J., Ruddle, F. H. Correction of a heat sensitive lesion associated with reduced leucyl-tRNA activity in Chinese hamster cells by fusion with human leucocytes. (Abstract) J. Cell Biol. 75: 387A only, 1977.
Giles, R. E., Shimizu, N., Ruddle, F. H. Assignment of a human genetic locus to chromosome 5 which corrects the heat sensitive lesion associated with reduced leucyl-tRNA synthetase activity in ts025/Cl Chinese hamster cells. Somat. Cell Genet. 6: 667-687, 1980. [PubMed: 6933703] [Full Text: https://doi.org/10.1007/BF01538645]
Han, J. M., Jeong, S. J., Park, M. C., Kim, G., Kwon, N. H., Kim, H. K., Ha, S. H., Ryu, S. H., Kim, S. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149: 410-424, 2012. [PubMed: 22424946] [Full Text: https://doi.org/10.1016/j.cell.2012.02.044]
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]
Yoon, I., Nam, M., Kim, H. K., Moon, H.-S., Kim, S., Jang, J., Song, J. A., Jeong, S. J., Kim, S. B., Cho, S., Kim, Y., Lee, J., and 12 others. Glucose-dependent control of leucine metabolism by leucyl-tRNA synthetase 1. Science 367: 205-210, 2020. [PubMed: 31780625] [Full Text: https://doi.org/10.1126/science.aau2753]