Alternative titles; symbols
HGNC Approved Gene Symbol: AIMP2
Cytogenetic location: 7p22.1 Genomic coordinates (GRCh38): 7:6,009,272-6,023,834 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.1 | Leukodystrophy, hypomyelinating, 17 | 618006 | Autosomal recessive | 3 |
The AIMP2 gene encodes an auxiliary nonenzymatic protein of the macromolecular multienzyme multi-tRNA synthetase complex (MSC), which is a housekeeping enzyme complex needed for translation of genetic information into functional proteins. AIMP2 acts as a scaffold required for the assembly and stability of the multi-tRNA synthetase complex. The MSC may also have additional roles in various signaling pathways (Kim et al., 2002; summary by Shukla et al., 2018).
In the process of characterizing PMS2 (600259) and its promoter region, Nicolaides et al. (1995) discovered another gene, designated JTV1, that is transcribed from the opposite strand and overlaps with PMS2. Both are ubiquitously expressed, as assayed by RT-PCR. JTV1 encodes a predicted 312-amino acid protein. The authors noted that protein sequence showed limited identity to the glutathione S-transferases (e.g., GSTM1; 138350).
In eukaryotes, 9 aminoacyl-tRNA synthetases contribute to a multienzyme complex of defined and conserved structural organization. This ubiquitous multiprotein assemblage comprises a unique bifunctional aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase (138295), as well as the monospecific isoleucyl- (600709), leucyl- (151350), glutaminyl- (603727), methionyl- (156560), lysyl- (601421), arginyl- (107820), and aspartyl- (603084) tRNA synthetases. Three auxiliary proteins of apparent molecular masses of 18, 38, and 43 kD are invariably associated with the 9 tRNA synthetase components of the complex. Quevillon et al. (1999) isolated the cDNA encoding the p38 non-synthetase component. By examination of genomic sequences, they showed that the 320-amino acid protein has no homolog in yeast, bacteria, or archaea. The p38 protein is a moderately hydrophobic protein, displays a putative leucine-zipper motif, and shares a sequence pattern with protein domains that are involved in protein-protein interactions. p38 was found to associate with itself to form a dimer, but also with p43, with the class I tRNA synthetases arginyl-tRNA synthetase (ArgRS) and GlnRS, with the class II synthetases AspRS and LysRS, and with the bifunctional GluProRS.
Nicolaides et al. (1995) determined that the JTV1 and PMS2 genes lie in a head-to-head arrangement. The JTV1 gene is transcribed from the opposite strand of the PMS2 gene.
The tRNA synthetase cofactor p38 was first identified as a factor associated with a macromolecular protein complex consisting of several different aminoacyl-tRNA synthetases (Quevillon et al., 1999). Kim et al. (2002) showed that p38 is a scaffold required for the assembly and stability of the multi-tRNA synthetase complex. Mice that were homozygous, but not heterozygous, with respect to mutations in p38 showed neonatal lethality, although they were born alive with the normal segregation ratio. Kim et al. (2003) investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38 was found to interact with FUSE-binding protein (FBP; 603444), a transcriptional activator of MYC (190080). Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of MYC, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (190180) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and MYC. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of MYC during lung differentiation. Alveolar type II cells are important for pulmonary respiration because they secrete surfactants that reduce the surface tension of water on the alveolar surface. Incomplete differentiation of these cells may cause respiratory distress syndrome, which occurs frequently in preterm infants and is a principal cause of their death.
Corti et al. (2003) demonstrated that parkin (602544), which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, and which is mutant in nearly 50% of patients with autosomal recessive early-onset parkinsonism (168600), interacts with, ubiquitylates, and promotes the degradation of p38. Ubiquitylation of p38 was abrogated by truncated variants of parkin lacking essential functional domains, but not by the pathogenic lys161-to-asn point mutant (602544.0008). Expression of p38 in COS-7 cells resulted in the formation of aggresome-like inclusions in which parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, parkin promoted the formation of ubiquitylated p38-positive inclusions. Overexpression of p38 in SH-SY5Y cells caused significant cell death against which parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of Lewy bodies in idiopathic Parkinson disease. The authors suggested that p38 may play a role in the pathogenesis of Parkinson disease.
Through an extensive profiling of adenosine-to-inosine RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples, Tan et al. (2017) identified AIMP2 as the top candidate negative regulator of editing. They showed that AIMP2 interacted with both ADAR1 (146920) and ADAR2 (601218), the primary editors of repetitive and nonrepetitive coding sites, respectively. Deletion mapping experiments showed that this interaction required residues 162-225 of AIMP2. Functional studies showed that AIMP2 promotes the degradation of ADAR1 and ADAR2, consistent with the findings of Kim et al. (2003), which showed a noncanonical function of AIMP2 in regulating protein stability. The results of gene perturbation experiments in a mouse myoblast cell line suggested that AIMP2 blocks ADAR1-mediated RNA editing, which has a role in the myoblast-to-myotube transition.
By virtue of the mapping of PMS2 by fluorescence in situ hybridization to 7p22, JTV1 must also lie at the same chromosomal location (Nicolaides et al., 1995).
In 4 patients from 2 unrelated consanguineous families of Indian descent with hypomyelinating leukodystrophy-17 (HLD17; 618006), Shukla et al. (2018) identified a homozygous nonsense mutation in the AIMP2 gene (Y35X; 600859.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant was in a common region of homozygosity in the families, suggesting a founder effect. Patient cells showed mildly decreased AIMP2 mRNA compared to controls, although the difference was not statistically significant. Additional functional studies were not performed.
Kim et al. (2002) found that mice with a homozygous mutation in the Aimp2 gene showed neonatal lethality, although they were born alive with the normal segregation ratio. Mutant mice had undetectable Aimp2 mRNA levels as well as decreased catalytic activity of complex-forming enzymes of the MSC compared to controls, suggesting that the Aimp2 mutation impaired stability and formation of the complex.
In 4 patients from 2 unrelated consanguineous families of Indian descent with hypomyelinating leukodystrophy-17 (HLD17; 618006), Shukla et al. (2018) identified a homozygous c.105C-A transversion (c.105C-A, NM_006303.3) in exon 1 of the AIMP2 gene, resulting in a tyr35-to-ter (Y35X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant was not found in the homozygous state in the 1000 Genomes Project, Exome Variant Server, ExAC database, or in an in-house database of local individuals. It was found in the heterozygous state at a very low frequency in the gnomAD database (1 in 227,386). The variant was in a common region of homozygosity in the families, suggesting a founder effect. Patient cells showed mildly decreased AIMP2 mRNA compared to controls, although the difference was not statistically significant. Additional functional studies were not performed.
Corti, O., Hampe, C., Koutnikova, H., Darios, F., Jacquier, S., Prigent, A., Robinson, J.-C., Pradier, L., Ruberg, M., Mirande, M., Hirsch, E., Rooney, T., Fournier, A., Brice, A. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum. Molec. Genet. 12: 1427-1437, 2003. [PubMed: 12783850] [Full Text: https://doi.org/10.1093/hmg/ddg159]
Kim, J. Y., Kang, Y.-S., Lee, J.-W., Kim, H. J., Ahn, Y. H., Park, H., Ko, Y.-G., Kim, S. p38 is essential for the assembly and stability of macromolecular tRNA synthetase complex: implications for its physiological significance. Proc. Nat. Acad. Sci. 99: 7912-7916, 2002. [PubMed: 12060739] [Full Text: https://doi.org/10.1073/pnas.122110199]
Kim, M. J., Park, B.-J., Kang, Y.-S., Kim, H. J., Park, J.-H., Kang, J. W., Lee, S. W., Han, J. M., Lee, H.-W., Kim, S. Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. Nature Genet. 34: 330-336, 2003. [PubMed: 12819782] [Full Text: https://doi.org/10.1038/ng1182]
Nicolaides, N. C., Kinzler, K. W., Vogelstein, B. Analysis of the 5-prime region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene. Genomics 29: 329-334, 1995. [PubMed: 8666379] [Full Text: https://doi.org/10.1006/geno.1995.9997]
Quevillon, S., Robinson, J.-C., Berthonneau, E., Siatecka, M., Mirande, M. Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein. J. Molec. Biol. 285: 183-195, 1999. [PubMed: 9878398] [Full Text: https://doi.org/10.1006/jmbi.1998.2316]
Shukla, A., Das Bhowmik, A., Hebbar, M., Rajagopal, K. V., Girisha, K. M., Gupta, N., Dalal, A. Homozygosity for a nonsense variant in AIMP2 is associated with a progressive neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis. J. Hum. Genet. 63: 19-25, 2018. [PubMed: 29215095] [Full Text: https://doi.org/10.1038/s10038-017-0363-1]
Tan, M. H., Li, Q., Shanmugam, R., Piskol, R., Kohler, J., Young, A. N., Liu, K. I., Zhang, R., Ramaswami, G., Ariyoshi, K., Gupte, A., Keegan, L. P., and 18 others. Dynamic landscape and regulation of RNA editing in mammals. Nature 550: 249-254, 2017. [PubMed: 29022589] [Full Text: https://doi.org/10.1038/nature24041]