Alternative titles; symbols
HGNC Approved Gene Symbol: GARS1
SNOMEDCT: 1197152005, 717011006;
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38): 7:30,594,735-30,634,033 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.3 | Charcot-Marie-Tooth disease, type 2D | 601472 | Autosomal dominant | 3 |
| Neuronopathy, distal hereditary motor, autosomal dominant 5 | 600794 | Autosomal dominant | 3 | |
| Spinal muscular atrophy, infantile, James type | 619042 | Autosomal dominant | 3 |
The GARS1 gene encodes glycyl-tRNA synthetase, an enzyme that is responsible for covalently attaching glycine to its cognate tRNA, which is essential for protein translation. Unlike most other tRNA synthetase genes, GARS1 encodes both the cytoplasmic and mitochondrial isoforms of the enzyme. The mitochondrial isoform contains a mitochondrial targeting signal (MTS) (summary by Boczonadi et al., 2018).
Aminoacyl-tRNA synthetases perform an essential function in protein synthesis by catalyzing the esterification of an amino acid to its cognate tRNA. These enzymes are necessarily present in each cell and must properly recognize the tRNA and the amino acid in order to maintain fidelity of translation. From the primary structures, 2 distinct classes of synthetases have been recognized, with similarity of certain structural features, amino acid attachment sites, and other properties between members of a class. Certain aminoacyl-tRNA synthetases are autoantigens in patients with the idiopathic inflammatory myopathies, polymyositis, and dermatomyositis. Autoantibodies reactive with synthetases are found almost exclusively in these conditions, with individuals usually having autoantibodies to only a single synthetase. Most commonly they are directed at histidyl-tRNA synthetase (142810), labeled 'anti-Jo-1' autoantibodies. Ge et al. (1994) used a cDNA encoding the human form of glycyl-tRNA synthetase for isolation of corresponding cDNAs. Shiba et al. (1994) likewise cloned a class II human glycyl-tRNA synthetase and compared its structure with that of the bacterial counterpart from which it was found to diverge widely.
Williams et al. (1995) also cloned the human GARS cDNA. The predicted 685-amino acid protein showed approximately 45% identity to the yeast protein. The recombinantly expressed protein was immunoprecipitated with human serum containing autoantibodies to glycyl-tRNA synthetase and was shown to catalyze the aminoacylation of tRNA.
Boczonadi et al. (2018) demonstrated that GARS1 localizes to mitochondrial RNA granules in human fibroblasts and oligodendroglial cells, indicating that it likely plays a role in mitochondrial translation. siRNA-mediated knockdown of the GARS1 gene resulted in reduced mitochondrial translation and decreased protein levels of respiratory chain subunits in oligodendroglial cells and myoblasts, but not in fibroblasts, suggesting tissue-specific functions. Detailed functional studies also suggested that GARS1 may have a noncanonical role in calcium metabolism, endoplasmic reticulum (ER) interactions, vesicle dynamics, and autophagy.
Nichols et al. (1995) mapped the GARS gene to chromosome 7p15 by FISH analysis.
Stumpf (2020) mapped the GARS1 gene to chromosome 17p14.3 based on an alignment of the GARS1 sequence (GenBank BC007755) with the genomic sequence (GRCh38).
Charcot-Marie-Tooth Disease Type 2D
Antonellis et al. (2003) identified heterozygous mutations in the GARS1 gene (e.g., 600287.0001) in families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472).
In 2 Malian sibs with CMT2D, Yalcouye et al. (2019) identified a heterozygous mutation in the GARS1 gene (S265Y; 600287.0012) by next-generation sequencing of a panel of 50 genes associated with CMT. The patients' mother also had the mutation but was asymptomatic, suggesting variable penetrance.
Distal Hereditary Motor Neuronopathy 5, Autosomal Dominant
Antonellis et al. (2003) identified heterozygous mutations in the GARS1 gene (e.g., 600287.0002) in families with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794).
In a patient (patient 1) and his mother with HMND5, Boczonadi et al. (2018) identified a heterozygous missense mutation in the GARS1 gene (H216R; 600287.0008). The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties.
In 7 unrelated patients with HMND5, Forrester et al. (2020) identified heterozygous missense variants in the GARS1 gene (see, e.g., H472R, 600287.0013). The variants, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in affected family members of 6 probands, whereas it occurred de novo in 1 patient. Although functional studies of the variants were not performed, 3 (H216R, G327R, and H472R) were classified as pathogenic or likely pathogenic, and 3 were considered to be of uncertain pathogenic significance (R27P, K510Q, and M555V), according to ACMG criteria.
Infantile Spinal Muscular Atrophy, James Type
In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; 619042), James et al. (2006) identified a de novo heterozygous missense mutation in the GARS1 gene (G598A; 600287.0007). Functional studies of the variant were not performed. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation.
In a 14-month-old infant (patient 2) with SMAJI, Forrester et al. (2020) identified a heterozygous missense mutation in the GARS1 gene (E125K; 600287.0009). The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed.
In 3 unrelated children with SMAJI, Markovitz et al. (2020) identified de novo heterozygous missense mutations in the GARS1 gene (I334N, 600287.0010 and G652R, 600287.0011). The mutations, which were found by trio-based exome sequencing, were not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast, consistent with a loss-of-function effect. Functional studies of the G652R variant were not performed.
Variant Function
Griffin et al. (2014) demonstrated that several missense mutations in the GARS gene previously associated with CMT2D and/or HMND5 had less than 10% aminoacylation activity compared to wildtype. These pathogenic mutations included G240R (600287.0001), G526R (600287.0004), D146N, S211F, P244L (600287.0006), I280F, H418R, and G598A (600287.0007). A57V retained about 50% residual activity. Site-directed mutagenesis studies in yeast showed that the D146N and P244L mutations resulted in a severe reduction in cell growth compared to wildtype. Finally, the S211F, P244L, I280F, and G598A mutant proteins did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of CMT2D and HMND5 pathogenesis. The findings were consistent with some of the mutations causing a loss of GARS function. However, the E71G (600287.0003) and D500N (600287.0005) mutations did not show impaired function in any of the assays used in the study.
He et al. (2015) determined that several mutations in the GARS gene that cause CMT2D, including G240R (600287.0001), L129P (600287.0002), and E71G (600287.0003), as well as a pro234-to-lys-tyr (P234KY) substitution in mouse, open a new protein-interaction surface on mutant GARS protein. Using in vitro protein pull-down and coimmunoprecipitation assays, the authors found that GARS(P234KY), GARS(L129P), GARS(G240R), and GARS(E71G) but not wildtype GARS, bound to NRP1 (602069), a VEGFA (192240) receptor required for motor neuron axon guidance and cell body migration. NRP1 coprecipitated GARS(P234KY) from mutant mice and GARS(L129P) in human lymphocytes much more readily than wildtype GARS. GARS(P234KY), but not wildtype GARS, competed with VEGFA for binding the extracellular b1 domain of NRP1.
Associations Pending Confirmation
McMillan et al. (2014) reported a 12-year-old girl, born of unrelated parents, with evidence of a systemic mitochondrial disorder. Exome sequencing identified compound heterozygous missense variants in the GARS1 gene (S635L and R596Q). Both variants occurred at highly conserved residues in the anticodon binding domain. The variants segregated with the disorder in the family: the unaffected mother carried the R596Q variant, whereas the father, who had a mild sensorimotor polyneuropathy, carried S635L. In addition, the proband carried a heterozygous variant in the MIB1 gene (608677), which is associated with left ventricular noncompaction-7 (LVNC7; 615092), which may have contributed to her cardiomyopathy. However, the MIB1 variant was also present in her father, who did not have cardiac disease. The patient had evidence of a systemic mitochondrial disorder, with exercise-induced myalgia, increased serum lactate and alanine, white matter abnormalities on brain imaging, and cardiomyopathy. Functional studies of the variants and studies of patient cells were not performed.
Boczonadi et al. (2018) performed functional studies of cells derived from the girl (patient 2) and her father (carrier 2) reported by McMillan et al. (2014). Although patient fibroblasts did not show a mitochondrial translation defect, induced neural progenitor cells derived from patient fibroblasts showed decreased levels of respiratory complex I subunit NDUFB8 (602140), as well as subtle defects in mitochondrial metabolism and fatty acid-beta oxidation. The authors postulated that recessive GARS1 variants may result in a loss-of-function effect with tissue-specific manifestations.
Oprescu et al. (2017) reported a 7-year-old girl (UDP5316), born of unrelated Caucasian parents, with a severe multisystem developmental disorder. Exome sequencing identified 2 variants in the GARS1 gene: a 4-bp deletion (c.246_249del), resulting in a frameshift and premature termination (Glu83IlefsTer6), and R310Q, which affected a conserved residue in the catalytic domain. Each unaffected parent carried 1 of the variants; neither variant was present in the gnomAD database. In vitro functional studies showed that both variants resulted in a loss-of-function effect on GARS1 activity. The patient was born at 36 weeks' gestation by cesarean section due to intrauterine growth retardation. She showed failure to thrive and global developmental delay, with independent walking at 6 years, pincer grasp at 5 years, and language delay with poor intelligibility. At age 3 years, she was microcephalic with abnormal skull shape and patent anterior fontanel. Dysmorphic features included sparse thin hair, triangular face with broad forehead, epicanthal folds, hypotelorism, smooth philtrum, and high-arched palate. She had upper motor neuron signs with hyperreflexia and spasticity of the lower limbs, but no evidence of lower motor neuron dysfunction or neuropathy. Sensation was normal. Additional features included retinal changes with depigmentation, sensorineural hearing loss, atrial septal defect, pulmonic stenosis, sleep apnea, atopic dermatitis, recurrent rhinitis, and fused cervical vertebrae. Brain imaging showed thin corpus callosum, mild atrophy of the cerebellar vermis, small brainstem, delayed myelination, and enlarged ventricles. Skeletal muscle biopsy was not performed.
Mouse
Using positional cloning, Seburn et al. (2006) found that a mutagenesis-induced dominant mouse model Nmf249 was caused by an in-frame indel mutation at pro278 in the Gars gene. Affected mice had a sensorimotor polyneuropathy with overt neuromuscular dysfunction by 3 weeks of age, smaller size, and shortened life spans compared to wildtype mice. Mutant mice showed neurodegenerative changes at the neuromuscular junction, with more severe changes at distal muscles. Nerve conduction velocities were severely decreased, and peripheral nerves showed reduced axonal diameters and loss of large-diameter axons, but no evidence of demyelination. Homozygous mutant mice were embryonic lethal. The affected pro278 residue is near the catalytic domain-2 of the protein, but the mutation did not affect Gars mRNA levels, and the recombinant mutant enzyme showed normal kinetics and activity. The findings were not consistent with either loss of function (haploinsufficiency) or a dominant-negative loss-of-function effect, but Seburn et al. (2006) postulated aberrant pathogenic function of the mutant protein.
He et al. (2015) found that mutant mouse embryos expressing Gars(P234KY) initially developed normally, but by embryonic day 13.5, they showed a defect in facial motor neuron migration. After birth, they developed CMT2D-like symptoms, including overt neuromuscular dysfunction and abnormal walking stride, which were accompanied by defects in neuromuscular junctions. He et al. (2015) observed that the phenotype was similar to that of Nrp1-null and Vegfa-null mice. Heterozygous knockout of Nrp1 in Gars(P234KY) mutant mice exacerbated the CMT2D symptoms, whereas enhanced expression of VEGF improved motor function. He et al. (2015) concluded that the Gars(P234KY) mutant interferes with Nrp1-Vegfa-dependent axon guidance cues during mouse neuronal development.
Spaulding et al. (2021) demonstrated impaired protein translation in motor neurons of mice with a dominant mutation in Gars (Gars C201R/+ or Gars P278KY/+). Interestingly, translation was not impaired in the liver or heart. Gene expression studies in the spinal cord motor neurons from the mutant mice demonstrated upregulated genes involved in the integrated stress response (ISR). The mutant mice were bred with Gcn2 (609280) homozygous knockout mice, and progression of neuropathy was prevented in the double mutant mice. Mutant Gars mice were also treated with a GCN2 inhibitor, and some improvement in motor performance and sciatic nerve conduction velocity was seen. Spaulding et al. (2021) concluded that mutations in GARS cause neuropathy by activating the ISR in a subset of neurons and that inhibiting GCN2 could be a therapeutic strategy.
Zuko et al. (2021) overexpressed tRNA Gly-GCC in mice with a heterozygous C201R mutation in the Gars gene. The overexpression of tRNA Gly-GCC completely prevented peripheral neuropathy in the mutant mice without affecting Gars mRNA and GlyRS protein levels. Furthermore, overexpression of RNA Gly-GCC in mice with a heterozygous delETAQ mutation in the Gars gene abrogated the activation of the integrated stress response in motor neurons that was seen in motor neurons of mice without overexpression of RNA Gly-GCC. This provided evidence that the mutant Gars sequesters tRNA Gly and depletes it for translation, which activates the ISR in motor neurons.
Zebrafish
Using a positional cloning strategy, Malissovas et al. (2016) identified a recessive lethal mutation in zebrafish gars, a thr209-to-lys (T209K) substitution equivalent to T130K in human GARS. T209 in zebrafish gars is located inside the catalytic domain at the dimer interface, and the T209K mutation affected gars homodimerization. Yeast complementation assays suggested that T209K is a loss-of-function mutation. In zebrafish larvae, homozygosity for T209K resulted in partial innervation and degeneration of fast muscle fibers in developing skeletal muscle. Loss of gars function prevented formation of functional cardiac valves at later stages of cardiac development. Further analysis confirmed that T209K caused loss of function, as the mutant protein was a monomer and could not catalyze ligation of glycine to its cognate tRNA, thereby impairing protein translation and causing the mutant phenotype in zebrafish. Wildtype zebrafish gars could rescue the neuromuscular phenotype in zebrafish homozygous for T209K, whereas expression of zebrafish gars with a gly319-to-arg (G319R) mutation, equivalent to the human mutation G240R (600287.0001) associated with reduced dimerization and aminoacylation, could not rescue the phenotype. Zebrafish gars with another mutation, G605R, equivalent to the human mutation G526R (600287.0004) that causes lack of enzymatic activity but retention of dimerization ability, also failed to rescue the phenotype of zebrafish homozygous for T209K. Zebrafish gars with a cys201-to-arg (C201R) mutation, equivalent to C236R in mouse Gars, which is unable to dimerize and partially lacks enzymatic activity, could rescue the phenotype of mutant zebrafish partially. Overexpression analysis in zebrafish heterozygous for T209K showed that dominant toxicity was associated with dimerization of the gars protein, as toxic potential of G605R was reduced when gars-G605R dimerized with gars-T209K. EGFP-tagged human GARS with T130K mislocalized in transfected mouse motor neurons, which was also subsequently confirmed by ectopic expression analysis of gars in zebrafish larvae.
In 2 families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) first reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997), Antonellis et al. (2003) identified a heterozygous c.1236G-C change in the GARS gene, resulting in a gly240-to-arg (G240R) substitution. The mutation was absent in 368 unrelated chromosomes.
In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794) first reported by Christodoulou et al. (1995), Antonellis et al. (2003) identified a heterozygous c.904C-T transition in the GARS gene, resulting in a leu129-to-pro (L129P) substitution. The mutation was absent in 376 unrelated chromosomes.
In a large family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), originally reported by Sambuughin et al. (1998), Antonellis et al. (2003) identified a heterozygous c.730A-G mutation in the GARS gene, resulting in a glu71-to-gly (E71G) substitution at a highly conserved residue. The mutation was absent in 398 unrelated chromosomes. Functional studies of the variant were not performed.
Variant Function
Griffin et al. (2014) found that the E71G variant did not impair GARS function in 3 in vitro assays: it had normal enzyme activity; yeast transfected with the variant showed normal growth; and the variant showed normal intracellular localization.
In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Antonellis et al. (2003) identified a heterozygous c.2094G-C mutation in exon 14 of the GARS gene, resulting in a gly526-to-arg (G526R) substitution. The mutation was absent in 360 unrelated chromosomes.
Dubourg et al. (2006) identified the G526R mutation in 12 affected members from 3 French families of Sephardic Jewish origin with HMND5. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect.
In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Del Bo et al. (2006) identified a heterozygous c.2016G-A transition in exon 13 of the GARS gene, resulting in an asp500-to-asn (D500N) substitution. The mutation was not identified in 100 control Italian individuals. There was broad intrafamilial phenotype variability, with some members presenting symptoms in childhood and some in adulthood. Sensory involvement was variable. Functional studies of the variant were not performed.
Variant Function
Griffin et al. (2014) found that the D500N variant did not impair GARS function in 2 in vitro assays: the variant had normal enzyme activity and showed normal intracellular localization.
In a Japanese patient with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), Abe and Hayasaka (2009) identified a heterozygous c.893C-T transition in the GARS gene, resulting in a pro244-to-leu (P244L) substitution in the catalytic domain. The mutation was not identified in 100 controls, is conserved among species, and was predicted to alter the secondary structure of the polypeptide. The patient had onset of the disorder in adolescence and early upper-limb involvement. No mutations in the GARS gene were found in 109 additional Japanese patients with axonal CMT, suggesting that GARS mutations are a rare cause of the disorder in this population.
In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; 619042), James et al. (2006) identified a de novo heterozygous c.2313G-C transversion in the GARS1 gene, resulting in a gly598-to-ala (G598A) substitution in the center of the anticodon binding domain. Functional studies of the variant were not performed, but the authors postulated a dominant-negative effect. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation.
In a pair of monozygotic twin girls with SMAJI, Eskuri et al. (2012) identified a de novo heterozygous c.1955G-C transversion in the GARS1 gene, resulting in a gly652-to-ala (G652A) substitution, which the authors stated was the same mutation as that reported by James et al. (2006). Functional studies of the variant were not performed, but the patients had a similar phenotype as the girl reported by James et al. (2006). The findings suggested that mutations in the anticodon binding domain may result in a severe phenotype with infantile onset.
Variant Function
Using in vitro studies, Griffin et al. (2014) demonstrated that the G598A mutation had less than 10% aminoacylation activity compared to wildtype. The G598A mutant protein did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of the pathogenesis.
In a patient (patient 1) and his mother with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Boczonadi et al. (2018) identified a heterozygous c.647A-G transition in the GARS1 gene, resulting in a his216-to-arg (H216R) substitution. The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties.
In a 14-month-old infant (patient 2) with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Forrester et al. (2020) identified a heterozygous c.373G-A transition (c.373G-A, NM_002047.2) in the GARS1 gene, resulting in a glu125-to-lys (E125K) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed. There was no mention of family history, segregation of the mutation, or genetic testing of the parents.
In 2 unrelated children (patients 1 and 2), both of Hispanic descent, with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Markovitz et al. (2020) identified a de novo heterozygous c.1001T-A transversion (c.1001T-A, NM_002047.2) in the GARS1 gene, resulting in an ile334-to-asn (I334N) substitution at a highly conserved residue in the catalytic domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast with deletion of this ortholog, consistent with a loss-of-function effect.
In a 14-month-old infant (patient 3) with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Markovitz et al. (2020) identified a de novo heterozygous c.1954G-C transversion (c.1954G-C, NM_002047.2) in the GARS1 gene, resulting in a gly652-to-arg (G652R) substitution at a highly conserved residue in the anticodon binding domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The affected residue was the same as that identified in other patients with a similar phenotype (600287.0007).
In 2 Malian sibs, aged 19 and 35 years, with axonal Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), who were born to consanguineous parents of Bambara ethnicity, Yalcouye et al. (2019) identified a c.794C-A transversion in the GARS1 gene, resulting in a ser265-to-tyr (S265Y) substitution in a conserved region of the protein. The patients' mother also had the mutation but was asymptomatic, suggesting incomplete penetrance. The mutation was identified by next-generation sequencing of a panel of 50 genes associated with CMT. The variant was not found in the ExAC, dbSNP, or 1000 Genomes Project databases.
In 3 affected members of a large multigenerational family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Forrester et al. (2020) identified a heterozygous c.1415A-G transition (c.1415A-G, NM_002047.2) in the GARS1 gene, resulting in a his472-to-arg (H472R) substitution. An unrelated patient (patient 6) with the disorder also carried the mutation. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was classified as pathogenic by ACMG criteria. Forrester et al. (2020) noted that Griffin et al. (2014) found that the H472R variant reduced aminoacyl-tRNA synthetase activity to 6.25% compared to wildtype.
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