Affinage

GARS1

Glycine--tRNA ligase · UniProt P41250

Length
739 aa
Mass
83.2 kDa
Annotated
2026-06-10
78 papers in source corpus 24 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GARS1 encodes glycyl-tRNA synthetase (GlyRS), a homodimeric class II aminoacyl-tRNA synthetase that charges tRNA^Gly with glycine; its crystal structure with bound tRNA^Gly and a glycyl-AMP intermediate captures the glycylation reaction and reveals the contributions of the flexible WHEP-TRS domain and characteristic insertions to tRNA binding (PMID:27261259). Dominant CMT2D-type peripheral neuropathy arises not from haploinsufficiency but from a dose-dependent toxic gain-of-function, since over-expression of wild-type GARS fails to rescue mutant mice while increased mutant dosage worsens disease (PMID:22144914). CMT2D mutations alter GlyRS conformation and confer neomorphic binding activities: mutant GlyRS aberrantly binds neuropilin-1, competitively antagonizing the VEGF-Nrp1 axis required for motor neuron survival (PMID:26503042), and aberrantly engages Trk neurotrophin receptors (TrkA/TrkB) to perturb sensory neuron fate during development (PMID:28351971), with downstream BDNF/TrkB-dependent disruption of axonal transport of signaling endosomes (PMID:36928301). A unifying biochemical mechanism is sequestration of tRNA^Gly by mutant GlyRS, which depletes the charged tRNA^Gly pool and stalls ribosomes at glycine codons (PMID:40119731). Wild-type GlyRS also binds and inhibits the deacetylase SIRT2 to maintain α-tubulin acetylation, an activity abolished by CMT2D mutations and whose restoration (via SIRT2 reduction) rescues neuropathy in flies (PMID:34053152); mutant neurotoxicity requires GlyRS dimerization (PMID:27008886) and is non-cell-autonomous (PMID:25972375). Recessive loss-of-function alleles instead cause a multisystem developmental syndrome and mitochondrial respiratory chain dysfunction (PMID:28675565, PMID:28594869). Beyond neuronal disease, GlyRS participates in nutrient-sensing mTOR signaling for milk synthesis (PMID:30171693, PMID:31954518) and a KLF16-GARS-FOXK1 glycolytic axis in hepatocellular carcinoma (PMID:40603105).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2006 Low

    Establishing which protein regions tolerate disease mutations was needed to map structure to pathology; identifying anticodon-binding-domain mutations extended the CMT2D/dSMA-V mutational spectrum beyond catalytic regions.

    Evidence Mutation screening and domain mapping in a 100-patient cohort

    PMID:17101916

    Open questions at the time
    • No biochemical assay of anticodon-binding activity for these variants
    • Genotype-phenotype correlation without mechanistic test
  2. 2009 Medium

    It was unclear whether heterozygous CMT2D pathology reflects reduced aminoacylation; a mouse point mutant showed enzyme deficits only in homozygotes, decoupling heterozygous disease from loss of charging activity.

    Evidence Gars^C201R mouse model with enzymatic assays and genetic crosses (SOD1^G93A, Dync1h1^Loa)

    PMID:19470612 PMID:19593442

    Open questions at the time
    • Mechanism of SOD1^G93A interaction unresolved
    • Does not identify the toxic activity itself
  3. 2011 High

    Distinguishing loss- versus gain-of-function was central to therapy; dosage experiments demonstrated dominant CMT2D is a toxic gain-of-function not corrected by wild-type supplementation.

    Evidence Transgenic wild-type GARS over-expression crossed into two dominant CMT2D mouse models with complementation tests

    PMID:22144914

    Open questions at the time
    • Does not define the molecular nature of the toxic activity
    • Restricted to two alleles
  4. 2013 Low

    Whether mutant GlyRS mislocalizes within neurons was tested; the G240R mutant failed to reach axonal compartments, hinting at a distribution defect linked to axonal degeneration.

    Evidence Adenoviral neuronal expression with immunohistochemical localization in mouse neurons

    PMID:23990368

    Open questions at the time
    • No functional rescue confirming mislocalization drives pathology
    • Single model, single lab
  5. 2015 High

    The neomorphic basis of toxicity was unknown; CMT2D conformational change was shown to create aberrant Nrp1 binding that antagonizes VEGF-Nrp1 motor-neuron survival signaling.

    Evidence Co-IP/competitive binding assays plus genetic epistasis (Nrp1 reduction, VEGF overexpression) in mice

    PMID:26503042

    Open questions at the time
    • Does not explain sensory phenotype
    • Relationship to aminoacylation defects unaddressed
  6. 2015 High

    Whether toxicity originates solely in neurons was tested; tissue-specific Drosophila expression showed mutant GlyRS in muscle/mesoderm alone causes WHEP-dependent NMJ denervation, establishing non-cell-autonomous pathology.

    Evidence Tissue-specific Drosophila CMT2D models with WHEP domain-deletion analysis and NMJ histology

    PMID:25972375

    Open questions at the time
    • Identity of the muscle-derived toxic signal not defined
    • WHEP domain mechanism not molecularly resolved here
  7. 2016 High

    A structural framework was lacking; the GlyRS-tRNA^Gly co-crystal with a glycyl-AMP intermediate defined the catalytic and WHEP-domain contributions to substrate engagement.

    Evidence X-ray crystallography at 2.95 Å of human GlyRS with tRNA^Gly

    PMID:27261259

    Open questions at the time
    • Does not model CMT2D mutant conformations
    • No structure of neomorphic complexes (Nrp1, Trk)
  8. 2016 High

    Whether the oligomeric state matters for toxicity was tested; dimerization was shown to be required for dominant neurotoxicity, distinguishing dominant-negative loss from gain-of-function alleles.

    Evidence Zebrafish genetic model with dimerization assays and rescue/complementation of multiple human-equivalent mutants

    PMID:27008886

    Open questions at the time
    • Mechanistic link between dimerization and neomorphic binding unspecified
    • Heterodimer composition in patients not addressed
  9. 2017 High

    The developmental component of CMT2D was unexplained; mutant GlyRS was found to aberrantly bind Trk receptors, misactivating signaling and skewing sensory neuron subtype balance at birth.

    Evidence In vitro wild-type vs mutant binding assays plus CMT2D mouse DRG subtype profiling

    PMID:28351971

    Open questions at the time
    • Quantitative contribution of Trk vs Nrp1 axes not separated
    • Structural basis of Trk binding unknown
  10. 2017 Medium

    The basis of recessive GARS disease was undefined; compound heterozygous loss-of-function variants were shown to cause a multisystem developmental syndrome distinct from dominant CMT2D.

    Evidence In vitro tRNA charging and protein expression analyses of patient frameshift and missense variants

    PMID:28675565

    Open questions at the time
    • Single patient/lab, limited replication
    • No animal model of the recessive syndrome
  11. 2017 Medium

    Tissue dysfunction in recessive disease needed a mechanism; loss-of-function GARS was linked to reduced activity of respiratory chain complexes I, III, and IV.

    Evidence Spectrophotometric respiratory chain assays and immunoblotting in patient muscle, liver, and fibroblasts

    PMID:28594869

    Open questions at the time
    • Causal pathway from GlyRS loss to complex deficiency not defined
    • Single patient cohort
  12. 2018 Medium

    An upstream regulator of GARS in neuronal development was sought; UBA1 was shown to act through a non-canonical, ubiquitylation-independent pathway controlling GARS-dependent sensory fate, linking SMA and CMT biology.

    Evidence Mass spectrometry target identification and UBA1 restoration epistasis in SMA mice

    PMID:30239612

    Open questions at the time
    • Biochemical mechanism of UBA1-GARS regulation uncharacterized
    • Direct physical interaction not established
  13. 2018 Medium

    A non-canonical signaling role was tested; GlyRS was shown to mediate amino acid-induced mTOR-S6K1/4EBP1 activation driving milk protein and fat synthesis.

    Evidence siRNA knockdown and overexpression in bovine mammary epithelial cells with pathway readouts

    PMID:30171693

    Open questions at the time
    • Single species/cell system
    • Direct mTOR-pathway interaction partner not reconstituted
  14. 2020 Medium

    How GlyRS is activated in nutrient signaling was unknown; a GPR87-CDC42/Rac1-MAP3K10 cascade was shown to phosphorylate GlyRS, promoting nuclear entry and milk-synthesis gene expression.

    Evidence Co-IP/MS, in vitro kinase assay, and pathway inhibition in bovine mammary epithelial cells

    PMID:31954518

    Open questions at the time
    • Phosphosite mapping incomplete
    • Non-neuronal, single-lab context
  15. 2020 Medium

    The spatial pattern of degeneration was undefined; NMJ denervation in CMT2D mice follows a distal-to-proximal gradient determined by post-natal synaptic growth rather than fiber type.

    Evidence Systematic multi-muscle NMJ histology and correlation analyses in CMT2D mice

    PMID:32703932

    Open questions at the time
    • Molecular driver of synaptic-growth vulnerability unidentified
    • Single lab
  16. 2020 Medium

    Site-specific sensory vulnerability lacked explanation; selectively elevated Gars expression in hindlimb-innervating sensory neuron subsets was linked to localized developmental defects.

    Evidence Anatomical dissection across multiple mouse models with subtype-specific Gars immunohistochemistry and axonal transport assays

    PMID:32848623

    Open questions at the time
    • Causal test of elevated Gars in vulnerability lacking
    • Single lab
  17. 2021 High

    A cytoskeletal function of GlyRS was identified; wild-type GlyRS binds and inhibits SIRT2 to preserve α-tubulin acetylation, an activity lost by CMT2D mutants and whose restoration rescues neuropathy.

    Evidence Reciprocal Co-IP, in vitro deacetylation assay, and SIRT2-knockdown rescue in Drosophila

    PMID:34053152

    Open questions at the time
    • Interplay with Nrp1/Trk neomorphic activities unresolved
    • Quantitative contribution to overall pathology unknown
  18. 2022 Low

    A shared structural consequence of mutations was sought computationally; MD simulations predicted G240R disrupts dimer-interface and tRNA-binding dynamics in a region commonly affected by CMT2D mutations.

    Evidence Molecular dynamics simulations of wild-type and G240R GlyRS

    PMID:36504507

    Open questions at the time
    • Computational only, no experimental validation
    • Single mutation modeled in detail
  19. 2023 High

    A downstream cellular defect of CMT2D was defined in vivo; early disturbance of axonal transport of neurotrophin endosomes was shown to be BDNF/TrkB-dependent and fully rescuable by muscle BDNF supplementation.

    Evidence Intravital sciatic-nerve imaging with TrkB inhibition and neurotrophin-specific rescue in CMT2D mice

    PMID:36928301

    Open questions at the time
    • Link between transport defect and SIRT2/tubulin axis unaddressed
    • Mechanism connecting mutant GlyRS to BDNF/TrkB at NMJ not fully resolved
  20. 2025 High

    A single unifying biochemical mechanism was sought across PN mutations; mutant GlyRS sequesters tRNA^Gly, depleting the charged pool and stalling ribosomes at glycine codons, while excluding dominant-negative loss-of-function and a non-pathogenic control variant.

    Evidence Drosophila PN-GlyRS models, de novo synthesis, tRNA sequestration, and aminoacylation assays with K456Q negative control

    PMID:40119731

    Open questions at the time
    • Relationship between sequestration and neomorphic receptor binding not integrated
    • Cell-type specificity of stalling not defined
  21. 2025 Medium

    A physiological role of the WHEP domain in vascular biology was identified; WHEP-dependent GlyRS secretion controls its Nrp1 interaction, and WHEP deletion drives aberrant Nrp1 endocytosis, VE-cadherin loss, and increased vascular permeability.

    Evidence Gars1^ΔWHEP knock-in mice, fractionation, Nrp1 Co-IP, endocytosis and VE-cadherin assays, Nrp1 heterozygous rescue (preprint)

    PMID:bio_10.1101_2025.05.14.654074

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Relation to CMT2D neuronal pathology unclear
  22. 2025 Medium

    A cancer-associated function was defined; a KLF16-GARS-FOXK1 axis was shown to promote hepatocellular carcinoma glycolysis via GARS stabilization of FOXK1 and induction of glycolytic genes.

    Evidence ChIP, Co-IP, ubiquitination assays, knockdown, and in vitro/in vivo glycolysis assays in HCC cells

    PMID:40603105

    Open questions at the time
    • Single-lab cancer context
    • Direct GARS-FOXK1 binding determinants not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple proposed mechanisms (tRNA^Gly sequestration, Nrp1 and Trk neomorphic binding, loss of SIRT2 inhibition, axonal transport disruption) are quantitatively integrated into a single dominant CMT2D pathogenic cascade remains unresolved.
  • No study reconciles relative contributions of each mechanism
  • Connection between aminoacylation-independent neomorphic activities and tRNA sequestration undefined
  • No structural model of any neomorphic complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 2 GO:0005576 extracellular region 1 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
FOXK1MAP3K10NRP1NTRK1NTRK2SIRT2UBA1

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 CMT2D mutations alter the conformation of GlyRS, enabling mutant GlyRS (GlyRS^CMT2D) to acquire a neomorphic binding activity that allows it to bind neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with VEGF binding to Nrp1, antagonizing the VEGF-Nrp1 signaling axis required for motor neuron survival. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced VEGF expression improves motor function. Co-IP/binding assays showing GlyRS^CMT2D-Nrp1 interaction; competitive binding with VEGF; genetic epistasis in mice (Nrp1 reduction, VEGF overexpression); conformational analysis of mutant vs. wild-type GlyRS Nature High 26503042
2011 The dominant CMT2D neuropathy caused by GARS missense mutations is due to a dose-dependent toxic gain-of-function mechanism, not loss of aminoacylation function. Over-expression of wild-type GARS does not rescue the neuropathy phenotype in heterozygous Gars mutant mice, demonstrating the pathology is not caused by haploinsufficiency. Increased dosage of disease-causing alleles worsened neuropathy, confirming a gain-of-function mechanism. Transgenic mice over-expressing wild-type GARS crossed to two dominant CMT2D mouse models; histological, functional, and behavioral assessment; complementation tests with null allele PLoS genetics High 22144914
2017 CMT2D mutant GlyRS aberrantly interacts with Trk neurotrophin receptors (TrkA and TrkB), causing misactivation of Trk signaling essential for sensory neuron differentiation and development. This interaction perturbs sensory neuron fate in dorsal root ganglia, leading to an imbalance of sensory neuron subtypes that is present at birth and non-progressive, indicating a developmental rather than purely degenerative insult. In vitro binding assays showing mutant but not wild-type GlyRS interacts with Trk receptors; mouse CMT2D model behavioral and histological analysis; sensory subtype profiling in DRG Proceedings of the National Academy of Sciences of the United States of America High 28351971
2015 Mutant GlyRS-induced neurotoxicity in CMT2D is non-cell autonomous: expression of mutant GlyRS in mesoderm or muscle alone (not just neurons) is sufficient to produce motor deficits and progressive neuromuscular junction (NMJ) denervation in Drosophila. The toxic gain-of-function effect is WHEP domain-dependent and is associated with abnormal NMJ assembly and pre-synaptic accumulation of mutant GlyRS. Novel Drosophila CMT2D models with tissue-specific (neuronal, mesodermal, muscle) expression of mutant GlyRS; motor deficit assays; NMJ histology; domain deletion analysis (WHEP domain) Human molecular genetics High 25972375
2016 Dimerization of GlyRS is required for dominant CMT2D neurotoxicity. A zebrafish loss-of-dimerization mutant (T209K/T130K in human) causes neuromuscular phenotype through loss of function. A human CMT disease-associated dimerization-deficient mutant (G319R/G240R in human) cannot rescue this phenotype, while another CMT mutant (G605R/G526 in human) that can dimerize with wild-type protein worsens phenotype in heterozygotes through dominant negative reduction of function. Zebrafish genetic model (gars^s266 allele); dimerization assays; rescue/complementation experiments with wild-type and mutant transgenes; neuromuscular phenotype assessment Human molecular genetics High 27008886
2016 Crystal structure of wild-type human GlyRS in complex with tRNA^Gly determined at 2.95 Å. The flexible WHEP-TRS domain is visible in one subunit of the homodimer; tRNA is fully resolved. A glycyl-AMP intermediate is present at the active site, capturing the enzyme in an intermediate stage of glycylation. The structure reveals the roles of insertions and the WHEP-TRS domain in tRNA binding. X-ray crystallography (2.95 Å); co-crystal of hGlyRS with tRNA^Gly; structural comparison with other class II aaRS-tRNA complexes Journal of molecular biology High 27261259
2025 tRNA^Gly sequestration by mutant GlyRS is the unifying pathogenic mechanism for all tested GARS1-associated peripheral neuropathy mutations. PN-mutant GlyRS variants (S211F and H418R) sequester tRNA^Gly, depleting the cellular tRNA^Gly pool, leading to insufficient glycyl-tRNA^Gly for ribosomes and ribosome stalling at glycine codons. A dominant negative loss-of-function mechanism was excluded for these variants. K456Q was shown not to be a pathogenic mutation as it does not affect aminoacylation or induce neuropathy in Drosophila. Novel Drosophila models expressing human PN-GlyRS variants; de novo protein synthesis assays; genetic and biochemical tRNA sequestration assays; aminoacylation activity measurements Nucleic acids research High 40119731
2021 Wild-type GARS binds the NAD+-dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in maintenance of acetylated α-tubulin. CMT2D mutations in GARS abolish this inhibitory interaction with SIRT2, leading to decreased acetylated α-tubulin. The catalytic domain of GARS mediates the interaction with SIRT2. Genetic reduction of SIRT2 in Drosophila CMT2D models rescues the axonal neuropathy phenotype. Co-IP of GARS and SIRT2; in vitro deacetylation assay; Western blotting for acetylated α-tubulin; Drosophila genetic rescue experiment with SIRT2 knockdown; domain analysis Aging cell High 34053152
2018 UBA1 regulates GARS via a non-canonical pathway independent of ubiquitylation. Dysregulation of the UBA1/GARS pathway in SMA mice disrupts sensory neuron fate, phenocopying GARS-dependent defects associated with CMT disease. Restoration of UBA1 corrects the sensory neuron fate defects and sensory-motor connectivity in SMA mice via the UBA1/GARS pathway. Mass spectrometry identification of GARS as UBA1 downstream target; genetic epistasis (UBA1 restoration in SMA mice); sensory neuron fate analysis; sensory-motor connectivity assessment Brain : a journal of neurology Medium 30239612
2018 GlyRS mediates amino acid (methionine and leucine)-induced activation of the mTOR-S6K1/4EBP1 signaling pathway in bovine mammary epithelial cells, thereby regulating milk protein and fat synthesis. GlyRS knockdown abolishes Met-stimulated milk synthesis, and GlyRS overexpression enhances it. siRNA knockdown and overexpression of GlyRS in bovine mammary epithelial cells; Western blotting and qRT-PCR for mTOR pathway components; milk protein/fat synthesis assays Journal of cellular physiology Medium 30171693
2020 MAP3K10 (mitogen-activated protein kinase 10) interacts with GlyRS in bovine mammary epithelial cells and acts as its upstream kinase. Met stimulates GlyRS phosphorylation via the GPR87-CDC42/Rac1-MAP3K10 signaling cascade. Phosphorylated GlyRS enters the nucleus to stimulate gene expression for milk synthesis, and MAP3K10 stimulates NFκB1 phosphorylation via GlyRS. Co-IP; mass spectrometry; Western blotting; in vitro kinase assay; pathway inhibition experiments Biochemical and biophysical research communications Medium 31954518
2009 The Gars^C201R point mutation in mice causes a heterozygous peripheral neuropathy with reduced enzyme (aminoacylation) activity only in homozygous animals, not heterozygotes, suggesting heterozygous pathology is not explained by reduced aminoacylation. Homozygous animals show a more severe phenotype consistent with partial loss of function. Genetic interaction with SOD1^G93A: the Gars^C201R mutation significantly delayed disease onset and extended lifespan by 29% in SOD1^G93A mice. Mouse genetic model characterization; enzymatic activity assays; genetic crosses with SOD1^G93A and Dync1h1^Loa mice; behavioral and electrophysiological assessments Disease models & mechanisms Medium 19470612 19593442
2017 Compound heterozygous GARS variants (frameshift p.Glu83Ilefs*6 and missense p.Arg310Gln) cause loss-of-function: the frameshift variant depletes protein levels and the missense variant reduces tRNA charging (aminoacylation) activity. This establishes that recessive GARS loss-of-function leads to a multisystem developmental syndrome with severe growth retardation, distinct from the dominant gain-of-function CMT2D mechanism. In vitro tRNA charging activity assays; protein expression analysis; in vivo functional studies; whole-exome sequencing with functional validation Human mutation Medium 28675565
2017 Compound heterozygous GARS variants cause mitochondrial respiratory chain dysfunction, with reduced activity of Complexes I, III, and IV in skeletal muscle and liver. Immunoblot analysis showed significant reduction in GARS protein and Complex IV subunits in patient fibroblasts, establishing a functional link between GARS loss-of-function and mitochondrial dysfunction. Spectrophotometric evaluation of mitochondrial respiratory chain complexes; immunoblot analysis of GARS protein and respiratory chain complex subunits; whole-exome sequencing PloS one Medium 28594869
2013 A disease-causing G240R mutation in GARS (G319R in zebrafish Gars) leads to altered intracellular distribution: wild-type GARS is distributed to peripheral axons, DRG cell bodies, central axon terminals, and motor neuron cell bodies, whereas G240R mutant GARS localizes only to DRG and motor neuron cell bodies but not axonal regions in vivo, suggesting a distribution defect associated with axonal degeneration. Adenoviral vector-mediated expression in mouse neurons using a neuronal-specific promoter; immunohistochemistry for GARS localization in vivo Journal of molecular histology Low 23990368
2023 CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo, correlating with BDNF/TrkB impairments. Inhibition of the BDNF/TrkB pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Supplementation with BDNF (but not other neurotrophins) completely restored physiological axonal transport in neuropathic mice. Intravital imaging of sciatic nerve in CMT2D mice; pharmacological TrkB pathway inhibition; BDNF muscle supplementation; neurotrophin-signaling endosome tracking JCI insight High 36928301
2020 In CMT2D mice, neuromuscular junction denervation occurs along a distal-to-proximal gradient. Defective NMJ development precedes and is associated with degeneration but is not linked to delay of wild-type NMJ maturation. The extent of post-natal synaptic growth (rather than muscle fibre type or synaptic architecture) predisposes to neurodegeneration at specific NMJs. Systematic comparison of NMJ development and degeneration across five wholemount muscles; correlation analyses of NMJ features with denervation severity; immunohistochemistry Cell death & disease Medium 32703932
2025 The WHEP domain of GlyRS (encoded by exon 2 of Gars1) is required for the free secretion/release of GlyRS from cells. Deletion of the WHEP domain (Gars1^ΔWHEP) causes GlyRS to accumulate in membrane fractions and show stronger interaction with the extracellular region of neuropilin 1 (Nrp1). This aberrant GlyRS-Nrp1 interaction enhances Nrp1 endocytic activity and reduces VE-cadherin localization at endothelial adherens junctions, increasing vascular permeability. Heterozygous Nrp1 knockout partially rescues the vascular permeability defects in Gars1^ΔWHEP/ΔWHEP mice. WHEP domain deletion did not impair tRNA aminoacylation. Gars1^ΔWHEP knock-in mice (exon 2 deletion); cell fractionation; co-IP with Nrp1 extracellular domain; endocytosis assays; VE-cadherin localization by immunofluorescence; genetic rescue with Nrp1 heterozygous knockout; aminoacylation activity assays bioRxivpreprint Medium bio_10.1101_2025.05.14.654074
2022 Molecular dynamics simulations of the G240R CMT2D mutation in GlyRS show altered native interactions at the dimer interface and altered dynamics of regions associated with tRNA binding. Computational analysis predicts that a region disrupted by G240R is commonly affected by multiple CMT2D mutations, suggesting a shared structural mechanism. Molecular dynamics simulations of wild-type and G240R mutant GlyRS; analysis of dimer interface contacts and tRNA-binding domain dynamics Brain multiphysics Low 36504507
2025 KLF16 binds to the GARS promoter and enhances its transcription in hepatocellular carcinoma cells. The GARS protein then binds to and stabilizes FOXK1 by reducing its ubiquitination. FOXK1 promotes glycolysis by stimulating transcription of LDHA, PKM2, and GLUT1. This KLF16-GARS-FOXK1 axis promotes HCC glycolysis and growth. Chromatin immunoprecipitation (KLF16 promoter binding); Co-IP (GARS-FOXK1 interaction); ubiquitination assays; knockdown experiments; in vitro and in vivo glycolysis assays The Tohoku journal of experimental medicine Medium 40603105
2006 Mutations in the anticodon binding domain of GARS (in addition to other domains) cause CMT2D/dSMA-V, establishing that the anticodon-binding domain is functionally important for disease causation. A mutation within the anticodon binding domain was associated with earlier childhood onset and predominantly lower limb involvement, extending the phenotypic spectrum. Mutation screening of 100 patients; identification and segregation of novel GARS missense mutations; domain mapping of mutation locations Neurology Low 17101916
2019 The p.Gly327Arg GARS variant fails to support yeast growth in a complementation assay, demonstrating loss-of-function at the level of aminoacylation activity. This establishes that severe impairment of GARS protein function causes distal hereditary motor neuropathy. Yeast complementation assay for GARS tRNA charging function Journal of the peripheral nervous system : JPNS Medium 31628756
2020 Sensory pathology in CMT2D mice is restricted to neurons innervating the hindlimbs. Gars expression is selectively elevated in a subset of sensory neurons and is linked to sensory developmental defects, providing a potential explanation for site-specific sensory vulnerability. Anatomical dissection of sensory nervous system in CMT2D mouse models; comparison across multiple mouse models of neuromuscular disease; in vitro axonal transport assays; immunohistochemistry for Gars expression in sensory neuron subsets Frontiers in cellular neuroscience Medium 32848623

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 136 26503042
1996 Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Human molecular genetics 105 8872480
2011 Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels. PLoS genetics 103 22144914
2009 An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy. Disease models & mechanisms 89 19470612
2014 Genetic Addiction Risk Score (GARS): molecular neurogenetic evidence for predisposition to Reward Deficiency Syndrome (RDS). Molecular neurobiology 88 24878765
2006 Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene. Neurology 76 17101916
2010 GARS axonopathy: not every neuron's cup of tRNA. Trends in neurosciences 64 20152552
1997 The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down syndrome. Human molecular genetics 62 9328467
2017 Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proceedings of the National Academy of Sciences of the United States of America 61 28351971
2006 Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation. Neurology 60 16534118
1998 Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. Journal of the neurological sciences 53 9879677
1982 Localization of neurons afferent to the optic tectum in longnose gars. The Journal of comparative neurology 50 7061736
2015 Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology. Human molecular genetics 43 25972375
2018 UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain : a journal of neurology 37 30239612
2012 Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V. Journal of the peripheral nervous system : JPNS 36 23279345
2021 High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial. Molecular neurobiology 35 33683627
2017 Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Human mutation 34 28675565
2018 GlyRS is a new mediator of amino acid-induced milk synthesis in bovine mammary epithelial cells. Journal of cellular physiology 31 30171693
2018 The Benefits of Genetic Addiction Risk Score (GARS™) Testing in Substance Use Disorder (SUD). International journal of genomics and data mining 29 30198022
2012 Infantile onset CMT2D/dSMA V in monozygotic twins due to a mutation in the anticodon-binding domain of GARS. Journal of the peripheral nervous system : JPNS 28 22462675
2021 AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in Gars mice. Brain communications 25 34755111
2020 Developmental demands contribute to early neuromuscular degeneration in CMT2D mice. Cell death & disease 24 32703932
2016 Genome Compositional Organization in Gars Shows More Similarities to Mammals than to Other Ray-Finned Fish. Journal of experimental zoology. Part B, Molecular and developmental evolution 24 28035749
2016 Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease. Human molecular genetics 23 27008886
2020 GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment. American journal of medical genetics. Part A 22 32181591
2015 Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease. PloS one 22 26244500
2012 Gene trees, species trees, and morphology converge on a similar phylogeny of living gars (Actinopterygii: Holostei: Lepisosteidae), an ancient clade of ray-finned fishes. Molecular phylogenetics and evolution 22 22445447
2023 Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice. JCI insight 21 36928301
2013 Coupling Genetic Addiction Risk Score (GARS) with Electrotherapy: Fighting Iatrogenic Opioid Dependence. Journal of addiction research & therapy 21 24616834
2010 Correlation between polymorphisms in ADSL and GARS-AIRS-GART genes with inosine 5'-monophosphate (IMP) contents in Beijing-you chickens. British poultry science 21 21058063
2009 The GARS gene is rarely mutated in Japanese patients with Charcot-Marie-Tooth neuropathy. Journal of human genetics 20 19329989
2017 Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. PloS one 18 28594869
2016 Crystal Structure of the Wild-Type Human GlyRS Bound with tRNA(Gly) in a Productive Conformation. Journal of molecular biology 18 27261259
2015 Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms. Journal of reward deficiency syndrome 18 27617300
2020 Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants. Journal of neuromuscular diseases 16 31985473
2022 Theorizing the Role of Dopaminergic Polymorphic Risk Alleles with Intermittent Explosive Disorder (IED), Violent/Aggressive Behavior and Addiction: Justification of Genetic Addiction Risk Severity (GARS) Testing. Journal of personalized medicine 15 36556167
2021 SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy. Aging cell 15 34053152
2019 A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease. Molecular genetics & genomic medicine 15 31173493
2020 Methionine stimulates GlyRS phosphorylation via the GPR87-CDC42/Rac1-MAP3K10 signaling pathway. Biochemical and biophysical research communications 14 31954518
2020 Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels. Frontiers in cellular neuroscience 14 32848623
2015 A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot-Marie-Tooth type 2D in a Chinese family. Neurological research 14 26000875
2022 Researching Mitigation of Alcohol Binge Drinking in Polydrug Abuse: KCNK13 and RASGRF2 Gene(s) Risk Polymorphisms Coupled with Genetic Addiction Risk Severity (GARS) Guiding Precision Pro-Dopamine Regulation. Journal of personalized medicine 13 35743793
2019 A recurrent GARS mutation causes distal hereditary motor neuropathy. Journal of the peripheral nervous system : JPNS 13 31628756
2009 Combined effect of mutations in ADSL and GARS-AIRS-GART genes on IMP content in chickens. British poultry science 12 19946821
2007 Potential interaction between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF transcription factor in Down syndrome-related Alzheimer disease. Cellular and molecular neurobiology 12 17902044
2021 Psychoactive Drugs Like Cannabis -Induce Hypodopaminergic Anhedonia and Neuropsychological Dysfunction in Humans: Putative Induction of Dopamine Homeostasis via Coupling of Genetic Addiction Risk Severity (GARS) testing and Precision Pro-dopamine Regulation (KB220). Neurology (E-Cronicon) 11 34085060
2010 Mutational analysis of glycyl-tRNA synthetase (GARS) gene in Hirayama disease. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 11 19412816
2009 Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice. PloS one 11 19593442
2005 Fine structural and cytochemical mapping of enamel organ during the enameloid formation stages in gars, Lepisosteus oculatus, Actinopterygii. Archives of oral biology 11 15748691
1999 The CMT2D locus: refined genetic position and construction of a bacterial clone-based physical map. Genome research 11 10400924
2018 Novel GARS mutation presenting as autosomal dominant intermediate Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS 10 30394614
2013 A novel adenoviral vector-mediated mouse model of Charcot-Marie-Tooth type 2D (CMT2D). Journal of molecular histology 10 23990368
2023 Phylogenomics of the Ancient and Species-Depauperate Gars Tracks 150 Million Years of Continental Fragmentation in the Northern Hemisphere. Systematic biology 9 36537110
2019 Typical bulbar ALS can be linked to GARS mutation. Amyotrophic lateral sclerosis & frontotemporal degeneration 9 30661401
2025 In Silico Pharmacogenomic Assessment of Glucagon-like Peptide-1 (GLP1) Agonists and the Genetic Addiction Risk Score (GARS) Related Pathways: Implications for Suicidal Ideation and Substance Use Disorder. Current neuropharmacology 8 39865816
2023 Glycyl-tRNA Synthetase (GARS) Expression Is Associated with Prostate Cancer Progression and Its Inhibition Decreases Migration, and Invasion In Vitro. International journal of molecular sciences 7 36901698
2018 Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V. Case reports in pediatrics 7 29527379
2002 Fine structure and Ca-ATPase activity of the stratum intermedium cells during odontogenesis in gars, Lepisosteus, Actinopterygii. Connective tissue research 7 12489205
2024 Insights into phenotypic variability caused by GARS1 pathogenic variants. European journal of neurology 6 39051710
2015 The Early Mediaeval manorial estate of Gars/Thunau, Lower Austria: An enclave of endemic tuberculosis? Tuberculosis (Edinburgh, Scotland) 6 25857936
2025 Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy. Nucleic acids research 5 40119731
2022 Future Newborns with Opioid-Induced Neonatal Abstinence Syndrome (NAS) Could Be Assessed with the Genetic Addiction Risk Severity (GARS) Test and Potentially Treated Using Precision Amino-Acid Enkephalinase Inhibition Therapy (KB220) as a Frontline Modality Instead of Potent Opioids. Journal of personalized medicine 5 36556236
2018 A Novel Mutation of GARS in a Chinese Family With Distal Hereditary Motor Neuropathy Type V. Frontiers in neurology 5 30083128
2021 Infantile-onset CMT2D/dSMA-V in a Chinese family with parental germline mosaicism for a novel mutation in the GARS1 gene. Molecular genetics & genomic medicine 4 34898052
2014 Immunohistochemical and Western blot analyses of collar enamel in the jaw teeth of gars, Lepisosteus oculatus, an actinopterygian fish. Connective tissue research 4 24611716
2024 An overview of the two-component system GarR/GarS role on antibiotic production in Streptomyces coelicolor. Applied microbiology and biotechnology 3 38656376
2022 Conformational sampling of CMT-2D associated GlyRS mutations. Brain multiphysics 2 36504507
2021 Inhibition of GARS1-DT Protects Against Hypoxic Injury in H9C2 Cardiomyocytes via Sponging miR-212-5p. Journal of cardiovascular pharmacology 2 34483291
2009 Phylogenetic analysis and in silico characterization of the GARS-AIRS-GART gene which codes for a tri-functional enzyme protein involved in de novo purine biosynthesis. Molecular biotechnology 2 19301155
2025 A Comprehensive 4-layered In Silico Pharmacogenomics Analysis of the Genetic Addiction Risk Severity (GARS) Test: Strong Genetic Evidence Supporting GARS as a Novel Personalized Pre-addiction Assessment Tool in the Opioid Crisis Era. Current pharmaceutical biotechnology 1 40247807
2025 KLF16-induced Increase of GARS Promotes Glycolysis in Hepatocellular Carcinoma by Stabilizing FOXK1. The Tohoku journal of experimental medicine 1 40603105
2024 Gars truly are 'living fossils,' massive DNA data set shows. Science (New York, N.Y.) 1 38452074
2023 Gene Repair of iPSC Line with GARS (G294R) Mutation of CMT2D Disease by CRISPR/Cas9. Current medical science 1 36932303
2012 No Evidence for Mutations that Deregulate GARS-AIRS-GART Protein Levels in Children with Down Syndrome. Indian journal of clinical biochemistry : IJCB 1 23277712
2025 Dopaminergic Homeostatic Therapy (DHT™) as a Putative Anti-Addiction Seeking Intervention and Early Identification of Genetic Preaddiction with Genetic Addiction Risk Severity (GARS®) Screening. Acta scientific neurology 0 40896766
2025 Beyond translation: systematic insight of the multifaceted roles of GARS1 in cellular biology and disease. Cell cycle (Georgetown, Tex.) 0 41392997
2024 Psychometric Properties of the Chinese Version of the Gilliam Autism Rating Scale-Third Edition (CV-GARS-3). Journal of autism and developmental disorders 0 39395122
2024 A familial form of Charcot-Marie-Tooth disease (type 2d) caused by a previously unreported variant in GARS1. Journal of neurogenetics 0 39599995

Missed literature

Know a paper Affinage missed for GARS1? Flag it for the maintainers and the community.

No submissions yet.