Alternative titles; symbols
HGNC Approved Gene Symbol: AARS1
SNOMEDCT: 719515001;
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:70,252,298-70,289,506 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | ?Leukoencephalopathy, hereditary diffuse, with spheroids 2 | 619661 | Autosomal dominant | 3 |
| Charcot-Marie-Tooth disease, axonal, type 2N | 613287 | Autosomal dominant | 3 | |
| Developmental and epileptic encephalopathy 29 | 616339 | Autosomal recessive | 3 | |
| Trichothiodystrophy 8, nonphotosensitive | 619691 | Autosomal recessive | 3 |
The AARS gene encodes alanyl-tRNA synthetase. Each of the amino acid synthetases catalyzes the attachment of their respective amino acids to the appropriate tRNA. The class II Escherichia coli and human alanyl-tRNA synthetases cross-acylate their respective tRNAs and require, for aminoacylation, an acceptor helix G3:U70 basepair that is conserved in evolution (Shiba et al., 1995).
Some of the amino acid synthetases are targets for autoantibodies in the autoimmune disease polymyositis/dermatomyositis (Nichols et al., 1995) including histidyl-RS (142810), threonyl-RS (187790), isoleucyl-RS (600709), glycyl-RS (600287) and alanyl-RS.
Shiba et al. (1995) reported the primary structure and expression of an active human alanyl-tRNA synthetase. The N-terminal 498 amino acids of the 968-residue polypeptide showed 41% identity with the E. coli protein. The human protein contains the class-defining domain of the E. coli enzyme, which includes the part needed for recognition of the acceptor helix G3:U70 basepair as an RNA signal for alanine. The authors concluded that mutagenesis, modeling, domain organization, and biochemical characterization of the E. coli protein are valid as a template for the human protein.
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 2 catalytic-null splice variants for AlaRS.
Chihade et al. (2000) presented data on AARS from an early eukaryote and other sources that were consistent with the notion that mitochondrial genesis did not significantly precede nucleus formation.
Guo et al. (2009) demonstrated that the C-Ala domain is universally tethered to the editing domain both in alanyl-tRNA synthetase and in many homologous free-standing editing proteins. Crystal structure and functional analyses showed that C-Ala forms an ancient single-stranded nucleic acid binding motif that promotes cooperative binding of both aminoacylation and editing domains to tRNA(Ala). In addition, C-Ala may have played an essential role in the evolution of alanyl-tRNA synthetases by coupling aminoacylation to editing to prevent mistranslation.
Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences. Throughout evolution, 2 editing checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, serine poses a bigger challenge than glycine. One checkpoint is the AlaRS editing center, and the other is from widely distributed AlaXps, free-standing, genome-encoded editing proteins that clear Ser-tRNA(Ala) (AARSD1; 613212). The paradox of misincorporating both a smaller (glycine) and a larger (serine) amino acid suggests a deep conflict for nature-designed AlaRS. Guo et al. (2009) showed the chemical basis for this conflict. Nine crystal structures, together with kinetic and mutational analysis, provided snapshots of adenylate formation for each amino acid. An inherent dilemma is posed by constraints of a structural design that pins down the alpha-amino group of the bound amino acid by using an acidic residue. This design, dating back more than 3 billion years, creates a serendipitous interaction with the serine hydroxide that is difficult to avoid. Apparently because no better architecture for the recognition of alanine could be found, the serine misactivation problem was solved through free-standing AlaXps, which appeared contemporaneously with early AlaRSs.
Nichols et al. (1995) mapped the alanyl-RS gene by fluorescence in situ hybridization to chromosome 16q22. By radiation hybrid panel analysis, Maas et al. (2001) mapped the AARS gene centromeric to the KARS gene (601421) and the ADAT1 gene (604230) in region 16q22.2-q22.3.
The folding of mRNA influences a diverse range of biologic events such as mRNA splicing and processing, and translational control and regulation. Because the structure of mRNA is determined by its nucleotide sequence and its environment, Shen et al. (1999) examined whether the folding of mRNA could be influenced by the presence of single-nucleotide polymorphisms (SNPs). They reported marked differences in mRNA secondary structure associated with SNPs in the coding region of 2 human mRNAs: alanyl-tRNA synthetase and replication protein A, 70-kD subunit (RPA70; 179835). Enzymatic probing of SNP-containing fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nucleotides away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, they found that the SNP exerted an allele-specific effect on the accessibility of its flanking site in the endogenous human RPA70 mRNA. The results demonstrated the contribution of common genetic variation through structural diversity of mRNA and suggested a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biologic function.
Axonal Charcot-Marie-Tooth Disease Type 2N
In affected members of a large French family with axonal Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al. (2010) identified a heterozygous mutation in the AARS gene (R329H; 601065.0001). Affected members of an unrelated affected French family were found to carry the same mutation. Haplotype analysis excluded a founder effect in these families.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011) identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
McLaughlin et al. (2012) identified a heterozygous R329H mutation in an Australian family with CMT2N.
Using purified recombinant proteins, Sun et al. (2021) found that none of 6 different CMT-causing mutations in ALARS affected the monomeric state of the protein or reduced protein stability. Two mutations close to the active site of ALARS, including N71Y, completely abolished tRNA aminoacylation activity, whereas the rest, including R329H, did not impact this activity. None of the 6 mutations affected the proofreading activity of ALARS. The crystal structure of the aminoacylation domain of the ALARS R329H mutant in complex with an analog of the reaction intermediate revealed that the active site of the R329H mutant was identical to that of the wildtype protein. Mutations in the aminoacylation and editing domains of ALARS, especially R329H, but not those in the C-Ala domain, increased the conformational flexibility of the ALARS protein. Further analysis showed a structural relaxation and opening effect caused by mutations in the aminoacylation and editing domains, but not by mutations in the C-Ala domain, with R329H inducing the largest conformational change. In addition, CMT mutations in the aminoacylation domain, but not those in the C-Ala or editing domains, gained a function to interact with NRP1 (602069), a receptor previously linked to CMT pathogenesis, and this gain of function was also observed in patient-derived lymphocytes carrying the R329H mutation. The b1 and b2 domains of NRP1 were responsible for interaction with the ALARS R329H mutant.
In affected members of 3 unrelated multigenerational families with CMT2N, Weterman et al. (2018) identified heterozygous missense mutations in the AARS1 gene (see, e.g., R326W, 601065.0008 and E337K, 601065.0009). The mutations, which were found by sequencing a targeted gene panel, segregated with the disorder in the families. In vitro functional expression studies in yeast showed that the R327W variant is a null allele, the S627L variant is a hypomorphic allele, and the E337K variant is a hypermorphic allele causing a gain-of-function effect. Morpholino knockout of the zebrafish aars gene caused morphologic abnormalities, including shortened body axis, smaller eyes, curved bodies, tail abnormalities, and mildly disorganized motor neuron branching. Expression of the human AARS1 mutations in zebrafish caused toxicity with morphologic defects and abnormalities in neural development, demonstrating that the mutations are pathogenic. The authors suggested that AARS1 mutations that cause CMT2N act in a dominant-negative manner, although a toxic gain-of-function mechanism was also suggested.
Developmental and Epileptic Encephalopathy 29
In 2 sibs of mixed European descent with developmental and epileptic encephalopathy-29 (DEE29; 616339), Simons et al. (2015) identified compound heterozygous missense mutations in the AARS gene (K81T, 601065.0003 and R751G, 601065.0004). An unrelated child with a similar phenotype was found to be homozygous for the R751G mutation. The mutations were found by whole-exome sequencing. In vitro studies showed that both mutations resulted in a significant reduction of AARS function.
In 2 sibs, born of unrelated parents, with DEE29, Nakayama et al. (2017) identified compound heterozygous mutations in the AARS1 gene (601065.0006 and 601065.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro studies showed that the mutations resulted in significantly decreased AARS1 protein levels, a reduction in catalytic activity, and a defect in editing activity causing misacylation. The findings were consistent with a loss of function.
Hereditary Diffuse Leukoencephalopathy 2
In 2 affected members of a large multigenerational Swedish family with hereditary diffuse leukoencephalopathy-2 (HDLS2; 619661), Sundal et al. (2019) identified a heterozygous missense mutation in the AARS1 gene (C152F; 601065.0010). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in unaffected family members, consistent with segregation of the mutation with the disorder in the family. Functional studies of the variant were not performed.
Nonphotosensitive Trichothiodystrophy 8
From a cohort of 34 patients with nonphotosensitive trichothiodystrophy (TTD) with multisystem phenotypes, who were negative for mutation in known TTD-associated genes, Botta et al. (2021) identified 2 unrelated patients with TTD (TTD8; 619691) who were compound heterozygous for missense mutations in the AARS1 gene (601065.0011-601065.0014). Functional analysis showed a marked reduction in AlaRS aminoacylation activity with the mutant proteins compared to controls. Screening the AARS1 gene in another 21 patients with a clinical diagnosis of TTD did not reveal further potential pathogenic variants.
Associations Pending Confirmation
For a discussion of a possible association between autosomal dominant distal hereditary motor neuronopathy (see HMND1, 182960) and variation in the AARS gene, see 601065.0005.
Lee et al. (2006) demonstrated that low levels of mischarged transfer RNAs can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. Lee et al. (2006) reported that the mouse 'sticky' (sti) mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. Lee et al. (2006) concluded that their findings demonstrated that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provided a novel mechanism underlying neurodegeneration.
Using positional cloning, Vo et al. (2018) identified Ankrd16 (618017) as a modifier that suppressed cerebellar cell degeneration in Aars sti/sti mice. Immunoprecipitation analyses revealed that Ankrd16 bound directly to the aminoacylation domain of Aars. Serine misactivated by Aars was captured by the lysine side chains of Ankrd16, corrected by the hydrolytic editing functions of Ankrd16, and removed from the pool for protein synthesis before it was transferred to tRNA and subsequently misincorporated into nascent peptides, which caused serine-mediated cell death in Aars sti/sti cells. Mouse Ankrd16 could bind E. coli Aars and reduce death of E. coli via the same mechanism. Deletion of Ankrd16 in brains of Aars sti/sti mice caused widespread protein aggregation and neuron loss. Vo et al. (2018) concluded that ANKRD16 is a coregulator of AARS that protects against assaults on translation fidelity and proteostasis in neurons.
Weterman et al. (2018) found that morpholino knockout of the zebrafish aars gene caused morphologic abnormalities, including shortened body axis, smaller eyes, curved bodies, tail abnormalities, and mildly disorganized motor neuron branching.
In affected members of 2 unrelated French families with autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al. (2010) identified a heterozygous 986G-A transition in exon 8 of the AARS gene, resulting in an arg329-to-his (R329H) substitution in the alpha-10 helix. This highly conserved residue is the ortholog of R314 in E. coli, which is 1 of the major determinants for binding and efficient aminoacylation of tRNAs. E. coli mutants in this residue showed significant reduction in enzyme activity due to reduced binding, but the authors also postulated that the mutation could result in qualitative errors and the binding of noncognate tRNAs. The R329H mutation was not found in 1,000 control chromosomes. Haplotype analysis excluded a founder effect.
McLaughlin et al. (2012) identified a heterozygous R329H mutation in affected members of an Australian family with CMT2N. The substitution occurs within a highly conserved residue in the tRNA-binding domain. Aminoacylation studies showed that the mutation reduced enzyme activity by about 50% and was unable to complement deletion in yeast viability studies. There did not appear to be a dominant-negative effect. Haplotype analysis of this family and the 2 reported by Latour et al. (2010) showed that the mutation occurred independently. Bisulfite sequencing indicated that the mutation occurred via methylation-mediated deamination of a CpG dinucleotide on the noncoding strand. The findings indicated that R329H is a recurrent loss-of-function mutation.
In affected members of a Taiwanese family with axonal Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Lin et al. (2011) identified a heterozygous mutation in the AARS gene, resulting in an asn71-to-tyr (N71Y) substitution in a highly conserved region in the catalytic domain. In vitro functional expression studies by McLaughlin et al. (2012) showed that the mutant N71Y protein had severe loss of enzymatic activity (4,130-fold decrease), and was unable to complement loss of AARS in yeast viability studies. There was marked variability in the age of onset (range, 11 to 45 years) and severity. The proband presented at age 51 years with slowly progressive weakness and atrophy of the legs that began at age 30 years after normal development. Physical examination showed marked atrophy and mild weakness of the muscles in the legs and feet, and milder atrophy and weakness of the intrinsic hand muscles. He had absent ankle reflexes, hyporeflexia, and mildly decreased distal sensation. His mother, brother, and son had a similar disorder. His 2 younger sisters and niece, who also carried the mutation, denied neurologic symptoms, but neurologic examination showed distal muscle mild atrophy, weakness in the intrinsic foot muscles, and generalized hyporeflexia in all of them.
In 2 sibs of mixed European descent with developmental and epileptic encephalopathy-29 (DEE29; 616339), Simons et al. (2015) identified compound heterozygous missense mutations in the AARS gene: a c.242A-C transversion (c.242A-C, NM_001605.2), resulting in a lys81-to-thr (K81T) substitution at a conserved residue in the aminoacylation domain, and a c.2251A-G transition, resulting in an arg751-to-gly (R751G; 601065.0004) substitution at a conserved residue in the editing domain. An unrelated child with a similar phenotype was found to be homozygous for the R751G mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not present in an in-house control dataset of more than 350 exomes. The c.242A-C mutation was not found in the dbSNP (build 141), 1000 Genomes Project, Exome Sequencing Project (ESP6500), or Exome Aggregation Consortium databases; the c.2251A-G mutation was found in the dbSNP database (rs143370729) and at a low frequency of less than 0.00005 in the Exome Aggregation Consortium database. In vitro studies showed that the K81T mutant had mildly defective aminoacylation activity due to a 2-fold increase in k(m) with no change in k(cat), whereas the R751G mutant had severely defective activity with a 2-fold decrease in k(m) and a 5-fold decrease in k(cat), yielding an overall 10-fold decrease in enzyme activity. Transfection of the mutations into the yeast ortholog ALA1 showed that K81T reduced growth and was a hypomorphic allele; R751G-associated growth was similar to wildtype. The patients had onset of refractory myoclonic epilepsy between 2 and 6 months of age.
For discussion of the c.2251A-G transition (rs143370729) in the AARS gene, resulting in an arg751-to-gly (R751G) substitution, that was found in compound heterozygous state in sibs with developmental and epileptic encephalopathy-29 (DEE29; 616339) by Simons et al. (2015), see 601065.0003.
This variant is classified as a variant of unknown significance because its contribution to autosomal dominant distal hereditary motor neuronopathy (dHMN) (see HMND1, 182960) has not been confirmed.
In 4 members of a Chinese family with variable expressivity of autosomal dominant dHMN, Zhao et al. (2012) identified a heterozygous c.2677G-A transition in exon 19 of the AARS gene, resulting in an asp893-to-asn (D893N) substitution at a highly conserved residue in the C-Ala domain. The mutation, which was found by screening of a panel of genes putatively involved in peripheral neuropathies, segregated with the phenotype in the family. The mutation was not present in the 1000 Genomes Project database, in 220 East Asian control chromosomes, or in 850 patients with inherited neuropathy. Functional studies of the variant were not performed. The phenotype was highly variable: the 16-year-old proband presented with mild distal lower limb weakness and atrophy at age 11 years; his grandmother presented with distal lower limb weakness and atrophy at age 55; and his father and paternal aunt were asymptomatic but showed mild atrophy and weakness of the lower limbs. All 4 mutation carriers had pes cavus, hypo- or areflexia of the lower limbs, normal sensory function, and lack of upper limb involvement. EMG of 3 of the mutation carriers showed a neurogenic pattern. However, all had normal sensory and motor nerve conduction velocities.
In 2 sisters, born of unrelated parents, with developmental and epileptic encephalopathy-29 (DEE29; 616339), Nakayama et al. (2017) identified compound heterozygous mutations in the AARS1 gene: a 1-bp duplication (c.2067dupC, NM_001605.2), resulting in a frameshift and premature termination (Tyr690LeufsTer3), and c.2738G-A transition, resulting in a gly913-to-asp (G913D; 601065.0007) substitution at a highly conserved residue in the C-terminal domain that is important for editing activity. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient-derived cells showed significantly decreased AARS1 protein levels, to 3 to 12% of controls; no truncated protein was detected. In vitro functional expression studies showed that the mutations caused an 85% and 73% reduction, respectively, in catalytic activity compared to controls, as well as a defect in editing activity causing misacylation. Of note, the G913D mutation retained editing activity, whereas the frameshift mutation disrupted editing activity. The findings were consistent with a loss of function. The patients had onset of infantile spasms and seizures in the first months of life associated with hypsarrhythmia on EEG; both patients were later diagnosed clinically with Lennox-Gastaut syndrome. The parents, who were each heterozygous carriers of one of the variants, were clinically unaffected.
For discussion of the c.2738G-A transition (c.2738G-A, NM_001605.2) in the AARS1 gene, resulting in a gly913-to-asp (G913D) substitution, that was found in compound heterozygous state in 2 sisters with developmental and epileptic encephalopathy-29 (DEE29; 616339) by Nakayama et al. (2017), see 601065.0006.
In affected members of a large multigenerational family (L21) with autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Weterman et al. (2018) identified a heterozygous c.976C-T transition (c.976C-T, NM_001605) in exon 8 of the AARS1 gene, resulting in an arg326-to-trp (R326W) substitution. The mutation, which was found by sequencing a custom gene panel, segregated with the disorder in the family. There was 1 obligate carrier who was unaffected. The mutation was found once in the ExAC database.
In 5 members of a 2-generational family (H19) with autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Weterman et al. (2018) identified a heterozygous c.1009G-A transition (c.1009G-A, NM_001605) in exon 8 of the AARS1 gene, resulting in a glu337-to-lys (E337K) substitution. The mutation, which was found by sequencing of a custom gene panel, segregated with the disorder in the family. In vitro functional studies showed that the E337K mutation caused increased catalytic activity, consistent with it being a hypermorphic allele.
In 2 affected members of a large multigenerational Swedish family with hereditary diffuse leukoencephalopathy-2 (HDLS2; 619661) originally reported by Axelsson et al. (1984), Sundal et al. (2019) identified a heterozygous c.455G-T transversion (c.455G-T, NM_001605.2) in the AARS1 gene, resulting in a cys152-to-phe (C152F) substitution at a conserved residue in the aminoacylation domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in unaffected family members, consistent with segregation of the mutation with the disorder in the family. The mutation was not present in the gnomAD database. Functional studies of the variant were not performed; patient cells showed expression of both alleles with no splicing defects.
In an 18-month-old Indian girl (TTD236AM) with nonphotosensitive trichothiodystrophy (TTD8; 619691), born of nonconsanguineous Indian parents, Botta et al. (2021) identified compound heterozygosity for missense mutations in the AARS1 gene: a c.2096T-C transition (c.2096T-C, NM_001605.3), resulting in an ile699-to-thr (I699T) substitution, and a c.2702G-A transition, resulting in a cys901-to-tyr (C901Y) substitution. Both substitutions occurred at highly conserved residues. The C901Y variant was not found in the gnomAD database, but the I699T variant was present at very low minor allele frequency (0.000003991). The patient had an affected older sister who died at age 9 years. DNA was unavailable for segregation analysis because the family was lost to follow-up. Immunoblot analysis of whole-cell lysates showed a reduction in AlaRS, to approximately 30% of the control amount, suggesting that the missense mutations affect protein stability. Steady-state aminoacylation reactions on protein lysates from patient fibroblasts showed only 10 to 20% of the AlaRS activity seen with control fibroblasts.
For discussion of the c.2702G-A transition (c.2702G-A, NM_001605.3) in exon 16 of the AARS1 gene, resulting in a cys901-to-tyr (C901Y) substitution, that was found in compound heterozygous state in an 18-month-old Indian girl (TTD236AM) with nonphotosensitive trichothiodystrophy (TTD8; 619691) by Botta et al. (2021), see 601065.0011.
In a 13-year-old Scottish boy (TTD1GL) with nonphotosensitive trichothiodystrophy (TTD8; 619691), originally reported by King et al. (1984), Botta et al. (2021) identified compound heterozygosity for missense mutations in the AARS1 gene: a c.2176A-G transition (c.2176A-G, NM_001605.3) in exon 15, resulting in a thr726-to-ala (T726A) substitution, and a c.2267C-T transition in exon 16, resulting in a thr756-to-ile (T756I) substitution. Both substitutions occurred at highly conserved residues. The T726A variant was not found in the gnomAD database, but the T756I variant was present at very low minor allele frequency (0.00001194). DNA was unavailable for segregation analysis because the family was lost to follow-up. The authors noted that the c.2176A-G mutation is located at the second base from the 3-prime end of exon 15, suggesting that it might affect splicing. Although no aberrantly spliced AARS1 transcript was detected, allele-specific assays showed that only 20% of transcripts were produced by the c.2176A-G allele. Immunoblot analysis of whole-cell lysates showed a reduction in AlaRS, to approximately 15% of the control amount, suggesting that the missense mutations affect protein stability. Steady-state aminoacylation reactions on protein lysates from patient fibroblasts showed only 10 to 20% of the AlaRS activity seen with control fibroblasts.
For discussion of the c.2267C-T transition (c.2267C-T, NM_001605.3) in exon 16 of the AARS1 gene, resulting in a thr756-to-ile (T756I) substitution, that was found in compound heterozygous state in a 13-year-old Scottish boy (TTD1GL) with nonphotosensitive trichothiodystrophy (TTD8; 619691) by Botta et al. (2021), see 601065.0013.
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