Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: Hum Mutat. 2022 Apr 21;43(7):869–876. doi: 10.1002/humu.24372

Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes

Alayne P Meyer 1,2, Megan E Forrest 3, Stefan Nicolau 4, Wojciech Wiszniewski 5, Mary Pat Bland 5, Chang-Yong Tsao 2,6,7, Anthony Antonellis 3,8, Nicolas J Abreu 2,4,6
PMCID: PMC9247498  NIHMSID: NIHMS1817157  PMID: 35332613

Abstract

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot–Marie–Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

Keywords: Charcot–Marie–Tooth disease, complementation assay, GARS1, missense variant, spinal muscular atrophy

GARS1 encodes glycyl-tRNA synthetase, which catalyzes the esterification of glycine to its cognate tRNA. Several variants in the gene have been associated with either loss- or gain-of-function effects; the former affecting GARS localization and tRNA charging (Antonellis et al., 2006; Grice et al., 2015; Griffin et al., 2014), and the latter affecting interactions with other proteins such as neuropilin-1 (NRP1; He et al., 2015) or initiating the integrated stress response via increased binding to tRNA (Mendonsa et al., 2021; Spaulding et al., 2021). While GARS1 is ubiquitously expressed, the associated disorders primarily form a spectrum of genetic axonopathies including Charcot–Marie–Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and non-5q infantile spinal muscular atrophy (iSMA; Antonellis et al., 2003; James et al., 2006). GARS1-related CMT2D and dHMN-V were first described in 2003 and often share initial symptoms of hand weakness and atrophy with onset in childhood or early adulthood. Distal lower limb weakness may also develop in a subset of patients (Antonellis et al., 2003; Forrester et al., 2020; Markovitz et al., 2020; Yalcouyé et al., 2019). The two conditions are differentiated by the presence of sensory disturbances in CMT2D (Antonellis et al., 2003; Chung et al., 2018; Del Bo et al., 2006; Forrester et al., 2020; Markovitz et al., 2020). iSMA due to GARS1 variants was initially described in 2006, and since then, 10 additional patients have been reported (Chung et al., 2018; Eskuri et al., 2012; Forrester et al., 2020; James et al., 2006; Liao et al., 2015; Markovitz et al., 2020). This more severe phenotype presents with symptoms beginning in the first 12 months of life and is generally associated with early respiratory failure and severe dysphagia (Chung et al., 2018; Forrester et al., 2020; Markovitz et al., 2020). The iSMA phenotype arises from variants in the anticodon binding and catalytic domains of the gene, but patients carrying other variants in these domains may also present with milder phenotypes (Chung et al., 2018; Eskuri et al., 2012; Forrester et al., 2020; James et al., 2006; Kawakami et al., 2014; H. J. Lee et al., 2012; Liao et al., 2015; Markovitz et al., 2020). Here we describe two previously unreported GARS1 variants affecting the p.Pro336 residue, resulting in iSMA in one patient and childhood-onset CMT2D in the second. Both patients provided informed consent for participation.

Patient 1 is a 20-year-old African American female born at term following an uncomplicated pregnancy and delivery. She had no family history of neuromuscular disease. In the first months of life, she had poor feeding, a weak cry, decreased spontaneous movement, and poor head control. She developed respiratory failure requiring tracheostomy at 5.5 months and has required continuous ventilation since that time. She also had dysphagia requiring gastrostomy. She never sat unsupported, rolled, or reached for objects. She underwent surgical correction of ankle contractures and scoliosis at 3 and 14 years, respectively. She had trace antigravity elbow flexion movements as a toddler but never attained a full range of motion.

Serial examinations demonstrated the progressive weakness of the face, trunk, and extremities, which was more pronounced distally and in the lower extremities. At 20 years of age, she had bilateral facial weakness, tongue fasciculations, diffuse atrophy, areflexia, contractures, and severe weakness of the extremities, limited to trace shoulder abduction, finger flexion, and head rotation (Figure 1a). There was no movement detected in the lower extremities. She had sensory loss to large fiber modalities (i.e., vibration, proprioception) in a stocking distribution. Her cognition was unaffected.

FIGURE 1.

FIGURE 1

Open in a new tab

(a) Clinical findings of Patient 1; note diffuse atrophy and distal contractures of four extremities with tracheostomy in situ requiring continuous ventilation and gastrostomy tube present (latter not shown). (b, c) Clinical findings of Patient 2; note atrophy of distal lower limb musculature and intrinsic hand muscles, with severe finger extension weakness and flexion contractures. (d, e) Sural nerve biopsy findings in Patient 1 from 5 months of age. (d) Occasional myelin digestion chambers were present (arrows). Hematoxylin and eosin stain, scale bar = 100 μm. (e) The density of large myelinated nerve fibers was mildly reduced and scattered axons showed signs of degeneration (arrows). Toluidine blue stain, scale bar = 25 μm. (f) Muscle biopsy performed at 2 years and 8 months of age in Patient 1 demonstrates small groups of atrophic fibers (arrows) and increased perimysial connective tissue (*). Hematoxylin and eosin stain, scale bar = 100 μm. (g, k) Functional studies of the p.Pro336His and p.Pro336Arg GARS1 variants. (g) The p.Pro336 amino acid is highly conserved from humans to bacteria (T. thermophilus). (h) Haploid yeast lacking endogenous GRS1 were rescued by wild-type human GARS1, but not by p.Pro336His or p.Pro336Arg GARS1, nor by a vector with no GARS1 insert (pYY1). Replicates A and B indicate yeast colonies obtained from two independent transformations. Image shown is representative of three independent transformations using three different plasmid DNA preparations. (i) (left) PyMOL model generated using a Protein Database (PDB) structural data file for GARS1 complexed with tRNA-Gly in a crystal lattice (Deng et al., 2016; PDB accession 4QEI). The model represents a monomer of GARS1 protein (light blue) complexed with a single tRNA-Gly (gray) for simplicity; note that GARS1 functions as a homodimer in vivo. (right) Enlarged and rotated view of GARS1 Pro336 (green) and surrounding residues within the GARS1 catalytic domain (Ser335 and Arg337, orange) along with the tRNA-Gly acceptor stem (G1, purple). (j, k) Enlarged and rotated views of the (j) GARS1 Pro336His and (k) Pro336Arg amino-acid substitutions modeled using PyMOL protein mutagenesis. Steric clashing with surrounding resides in neighboring areas of the GARS1 catalytic domain are indicated by orange dashed lines

She underwent muscle and sural nerve biopsies at 5 months of age, and again at 2 years and 8 months of age. Sural nerve pathology showed axonal degeneration (Figure 1d, e), while muscle pathology revealed denervation (Figure 1f). Electrodiagnostic studies at 5 years of age showed a severe axonal neuropathy with absent motor responses in the distal upper and lower extremities, and absent sensory responses in the lower extremities. An 83-gene nextgeneration sequencing panel for inherited neuropathies (including genes associated with Charcot–Marie–Tooth disease, hereditary motor neuropathy, and hereditary sensory and autonomic neuropathies) identified a de novo missense variant in GARS1: c.1007C > G (p.Pro336Arg). No additional variants were identified on this testing.

Patient 2 is a 41-year-old male of European ancestry. As a child, he was noted to have pes planus and to run more slowly than his peers. At age 10, he developed finger extension weakness and intrinsic hand muscle atrophy. He required multiple tendon transfers in his hands between the ages of 13–25 due to progressive weakness. He developed lower extremity symptoms including foot drop, worsening pes planus, and distal muscle atrophy, requiring ankle-foot orthotics starting at age 13. Respiratory involvement and dysphagia were absent.

Neurological examination of Patient 2 demonstrated asymmetric distal upper extremity weakness and symmetric distal lower extremity weakness (Figure 1b, c). There was no facial weakness. Deep tendon reflexes were reduced proximally and absent distally. Mild distal sensory loss was present. He was noted to have a mild tremor and a steppage gait. Electrodiagnostic studies performed at ages 19 and 27 revealed a motor axonal neuropathy or neuronopathy with minimal sensory abnormalities. The patient's family history was significant for neuropathy in his sister, brother, mother, and niece. The onset of disease was by 10 years of age in his sister, brother, and niece, while his mother had symptom onset in her early forties. A 24-gene next-generation sequencing panel for distal hereditary motor neuropathies identified a missense variant in the GARS1 gene: c.1007C > A (p.Pro336His). This variant was present in all affected family members and absent in the patient's unaffected father. No additional variants were identified on this testing.

Patients 1 and 2 both harbor variants affecting GARS1 p.Pro336, which is located within a stretch of highly conserved residues (including between humans and bacteria) in the catalytic domain of the protein (Figure 1g). Previous studies have shown that human GARS1 is sufficient to rescue deletion of the yeast glycyl-tRNA synthetase ortholog GRS1 using yeast complementation assays, and this system has been used to characterize other pathogenic, loss-of-function variants in GARS1 (D. C. Lee et al., 2019; Oprescu et al., 2017). We therefore used this system to assess the functional impact of the p.Pro336His and p.Pro336Arg variants. In these assays, the empty pYY1 vector was not sufficient to support yeast growth, indicating that GRS1 is essential for yeast survival. Yeast cells transformed with wild-type GARS1 showed appreciable growth at 30°C, indicating that expression of human GARS1 complements deletion of yeast GRS1 (Figure 1h). In contrast, neither p.Pro336His nor p.Pro336Arg GARS1 supported yeast growth at 30°C, suggesting that p.Pro336His and p.Pro336Arg represent loss-of-function alleles.

To further demonstrate the impact of the p.Pro336His and p.Pro336Arg variants in the context of the previously defined GARS1 protein structure, we performed single amino-acid mutagenesis in a 3D structural model of GARS1 complexed with tRNA-Gly using PyMOL (The PyMOL Molecular Graphics System, Schrödinger, LLC). Importantly, the two GARS1 residues immediately flanking the p.Pro336 residue (p.Ser335 and p.Arg337) are known to be important for recognition of the tRNA-Gly acceptor stem by forming direct contacts with Guanine 1 and Cytosine 72 (Figure 1i; reported as p.Ser281 and p.Arg283, respectively, in the original text; Qin et al., 2014). Mutagenesis of p.Pro336 to histidine or arginine in silico (Figure 1j, k) demonstrated extensive steric clashing with surrounding residues, suggesting that these variants are likely disruptive to the overall conformation of the GARS1 catalytic domain and potentially disruptive to tRNA-Gly substrate recognition.

Patient 1 represents the 12th individual reported with infantile onset disease due to variants in GARS1 (Table 1). All patients reported to date had variants in the catalytic (n = 8) or anticodon binding (n = 4) domains, which were de novo (n = 8) or inherited from an asymptomatic mosaic parent (n = 3). To the best of our knowledge, Patient 1 is also the oldest reported patient with infantile-onset disease, demonstrating that patients with GARS1-related iSMA can live into adulthood with supportive care. Even among people with GARS1-related iSMA, there exists significant variability in disease severity. Age of onset generally correlated with motor function and respiratory involvement. Five of six children presenting before 6 months of age required mechanical ventilation and either lost or never acquired independent sitting. By contrast, most individuals presenting at 6 months of age or older achieved and maintained independent sitting. Three could ambulate with a walker. Severe respiratory involvement can nonetheless occur in later-onset patients as well, as illustrated by two children who presented at 7 and 10 months of age and required ventilatory support. The phenotype of GARS1-related iSMA can be distinguished from SMN1-related SMA by preferential involvement of distal rather than proximal muscles, as well as the greater frequency of respiratory involvement during infancy in patients who achieve independent sitting. Other commonly reported symptoms among patients with GARS1-related iSMA included hypophonia, lordosis, scoliosis, ankle contractures, fasciculations, distal hyperlaxity, vocal cord dysfunction, and facial weakness. Sensory impairment was noted clinically in three and electrodiagnostically in five individuals, although many were too young for this to be assessed clinically. Electromyography in nearly all patients showed a motor axonal neuropathy or neuronopathy with variable degrees of sensory involvement. Muscle pathology in most patients was consistent with neurogenic atrophy.

TABLE 1.

Summary of infantile spinal muscular atrophy patients due to GARS1 variants (All NM_002047.2/NP_002038.2)

Variant Inheritance Domain Age
of
onset		 Age at last
examination		 Highest gross motor
function (age
attained)		 Respiratory
failure (Y/N)
(age started)		 G-tube
(Y/N)
(age
started)		 Other reported features EMG/NCS Muscle biopsy Source
c.373G > A (p.Glu125Lys) De novo Catalytic 3m NR NR Y (7m) Y (7m) Distal > proximal weakness Severe motor neuropathy/neuronopathy without sensory involvement NR Farwell et al. (2015), Forrester et al. (2020)
c.598G > T (p.Asp200Tyr) De novo Catalytic 3m 9y Sit unsupported (15m) N (temporarily at 3m with pneumonia) N Pes planus, distal > proximal weakness, sensory impairment Severe sensorimotor neuropathy NR Liao et al. (2015)
c.815T > G (p.Leu272Arg) Maternal mosaicism Catalytic 10m 2y Sit unsupported (24m) Y (10m) Y (12m) Distal hyperlaxity Motor axonal neuropathy/neuronopathy without sensory involvement Denervation atrophy Chung et al. (2018)
c.815T > G (p.Leu272Arg) Maternal mosaicism Catalytic 7m 7m NR Y (7m) NR Distal hyperlaxity NR NR Chung et al. (2018)
c.815T > G (p.Leu272Arg) Maternal mosaicism Catalytic 9m 4y Normal motor development (9m) N N Distal hyperlaxity Normal sensory function NR Chung et al. (2018)
c.1001T > A (p.Ile334Asn) De novo Catalytic 2m 11m Less than antigravity in lower extremities (11m) Y (3m) Y Oligohydramnios, fasciculations, proximal > distal weakness Predominantly motor axonal neuropathy/neuronopathy with mild sensory involvement Denervation atrophy Markovitz et al. (2020)
c.1001T > A (p.Ile334Asn) De novo Catalytic 1.5m 3.25y Rolled (3m, lost at 18m), sit unsupported (12m, lost at 39m) Y (2m) Y Distal > proximal weakness, claw-like hands, pes cavus, ankle contractures, sensory impairment, kyphoscoliosis, mildly increased prominence of CSF spaces Severe sensorimotor axonal neuropathy predominantly affecting motor fibers Denervation atrophy with features of chronic active myopathy Markovitz et al. (2020)
c.1007C > G (p.Pro336Arg) De novo Catalytic <5m 20y Head control, antigravity elbow flexion Y (5m) Y (6m) Scoliosis, distal > proximal weakness, facial weakness, hypophonia, fasciculations, contractures, sensory impairment, ankle contractures, dysconjugate gaze, high palate, crowded dentition, tented upper lip Severe axonal sensorimotor neuropathy Denervation atrophy Current study
c.1954G > C (p.Gly652Arg) De novo Anticodon binding Birth 14m Movement of arms/legs (lost) Y (4m) Y Vocal cord paralysis, distal progressing to proximal weakness, tongue fasciculations Severe sensorimotor neuropathy predominantly affecting motor fibers NR Markovitz et al. (2020)
c.1955G > C (p.Gly652Ala) Presumed de novo Anticodon binding 6m 7y Sit unsupported (6m), walk with walker (18m) N (FVC 80%) N Hypophonia, facial weakness, weak cough, hyperlordosis, preserved proximal strength EMG consistent with denervation Denervation atrophy James et al. (2006)
c.1955G > C (p.Gly652Ala) De novo Anticodon binding 6m 3.75y Walk with walker NR NR Hyperlordosis, vocal cord dysfunction, height/weight <1st% NR Fiber size variability and marked type I fiber predominance Eskuri et al. (2012)
c.1955G > C (p.Gly652Ala) De novo Anticodon binding 6m 3.75y Walk with walker NR NR Hyperlordosis, kyphoscoliosis, vocal cord dysfunction, height/weight <1st% Motor axonal neuropathy/neuronopathy NR Eskuri et al. (2012)
Open in a new tab

Abbreviations: CSF, cerebrospinal fluid; EMG/NCS, electromyography/nerve conduction studies; FVC, forced vital capacity; m, months; N, no; NR, not reported; y, years; Y, yes.

Our data revealed two different GARS1 variants affecting the same amino-acid residue that resulted in distinct phenotypes. While the cause for this discordance remains unclear, this sensitivity to specific amino-acid substitutions has previously been described at three other residues in GARS1. The iSMA patient reported by Liao et al. (p.Asp200Tyr; Table 1) had the same residue altered as several members of a Korean family with adolescent-onset dHMN (p.Asp200Asn; H. J. Lee et al., 2012). Three siblings with iSMA reported by Chung et al. (p.Leu272Arg; Table 1) had the same amino-acid position altered as a patient with childhood-onset CMT2D who developed facial weakness and involvement of bulbar and respiratory muscles in her thirties (p.Leu272Gln, reported as p.Leu218Gln in the original text; Kawakami et al., 2014). Finally, two unrelated patients with iSMA reported by Markovitz et al. (p.Ile334Asn; Table 1) carried a variant affecting the same p.Ile334 residue as seen reported in a family with adolescent-onset dHMN-V (p.Ile334Phe, reported as p.Ile280Phe in the original text for Family 3; James et al., 2006).

These clinical differences raise questions about the underlying molecular mechanism of each mutation. For missense variants that affect the same codon, differential effects on protein function are sometimes explained by the degree of biochemical differences between the wild-type and mutant amino-acids (de Beer et al., 2013; Markovitz et al., 2020; Vitkup et al., 2003). In the present report, both variants resulted in changes to sterically large, positively charged amino acids (histidine or arginine) in place of the nonpolar proline residue resulting in clashing with other nearby amino-acid residues (Figure 1j, k), and both variants were associated with loss-of-function effects in a yeast model of GARS1 function (Figure 1h). The observed phenotypic differences may be explained in part by the degree of disruption of the original nonpolar proline residue, where substitution of the more highly charged arginine residue was associated with a more severe iSMA phenotype versus the CMT2D phenotype associated with substitution of a less basic histidine residue. While the in vivo and in silico functional studies presented here were not sufficient to differentiate the effects of these two amino-acid substitutions, careful analysis of tRNA-Gly substrate binding kinetics by more quantitative tRNA binding assays (e.g., electrophoretic mobility shift assays with labeled tRNA-Gly) could provide an explanation for differences in the observed phenotypes associated with these variants.

It is also important to consider the effects of the two different missense variants reported here in the context of proposed molecular mechanisms underlying aminoacyl-tRNA synthetase-related peripheral neuropathy. First, a dominant-negative mechanism has been proposed for loss-of-function missense alleles in cytoplasmic homodimeric aminoacyl-tRNA synthetases (Meyer-Schuman & Antonellis, 2017). Here, different amino-acid substitutions at the same residue could result in differing degrees of suppression of the wild-type protein (e.g., variable affinity for the wild-type protein). Second, GARS1 functions in the cytoplasm and mitochondria, and the different amino-acid substitutions may differentially affect mitochondrial import and/or tRNA charging in this organelle. Third, gain-of-function mechanisms have been proposed, which involve aberrant interactions between mutant GARS1 and other proteins (e.g., NRP1; He et al., 2015) or between mutant GARS1 and cognate tRNA molecules (Mendonsa et al., 2021; Spaulding et al., 2021). Therefore, different amino-acid substitutions at the same residue could result in different affinities for these proteins or tRNAs. Regarding the latter interactions, it has been proposed that increased tRNA binding results in activation of the integrated stress response (Spaulding et al., 2021), with neurons being more susceptible to the downstream effects of this pathway. Finally, phenotypic differences could be explained by additional variants in other unidentified loci that could serve to modify GARS1 function, therefore modifying the effects of the observed disease-causing gene mutations on downstream biochemical pathways.

In summary, we have identified two previously unreported disease-causing variants that alter the same amino-acid residue (p.Pro336His and p.Pro336Arg) in GARS1 and provided in vivo and in silico evidence of their deleterious effect on GARS1 function. The two variants led to distinct neuropathic phenotypes ranging from iSMA to CMT2D, but further work is needed to clarify the molecular mechanisms underlying these phenotypic differences.

Supplementary Material

Supplementary material

ACKNOWLEDGMENTS

The authors are grateful to the affected individuals and their families for participating in this study. We would also like to thank Chin-I Chien and Chien-Chia Wang (National Central University, Taiwan) for the pYY1 expression construct. A.A. is supported by a grant from the National Institute of General Medical Sciences (GM136441). M.E.F. is supported by a Neurology Training Grant from the National Institutes of Health (5T32NS007222-40).

Footnotes

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

Additional clinical data or findings are available from the authors upon reasonable request. The GARS1 p.Pro336Arg variant has been submitted to ClinVar, accession number VCV001067545.2 (https://www.ncbi.nlm.nih.gov/clinvar/). The GARS1 p.Pro336His has been submitted to ClinVar, submission identification number SUB11111758 (https://www.ncbi.nlm.nih.gov/clinvar/).

REFERENCES

  1. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, & Green ED (2003). Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. American Journal of Human Genetics, 72(5), 1293–1299. 10.1086/375039 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung K, Burgess S, Fischbeck KH, & Green ED (2006). Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. Journal of Neuroscience, 26(41), 10397–10406. 10.1523/JNEUROSCI.1671-06.2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chung P, Northrup H, Azmath M, Mosquera RA, Moody S, & Yadav A (2018). Glycyl tRNA synthetase (GARS) gene variant causes distal hereditary motor neuropathy V. Case Reports in Pediatrics, 2018, 1–4. 10.1155/2018/8516285 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. de Beer TAP, Laskowski RA, Parks SL, Sipos B, Goldman N, & Thornton JM (2013). Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 Genomes Project Dataset. PLoS Computational Biology, 9(12), e1003382. 10.1371/journal.pcbi.1003382 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Del Bo R, Locatelli F, Corti S, Scarlato M, Ghezzi S, Prelle A, Fagiolari G, Moggio M, Carpo M, Bresolin N, & Comi GP (2006). Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation. Neurology, 66(5), 752–754. 10.1212/01.wnl.0000201275.18875.ac [DOI] [PubMed] [Google Scholar]
  6. Deng X, Qin X, Chen L, Jia Q, Zhang Y, Zhang Z, Lei D, Ren G, Zhou Z, Wang Z, Li Q, & Xie W (2016). Large conformational changes of insertion 3 in human glycyl-tRNA synthetase (hGlyRS) during catalysis. Journal of Biological Chemistry, 291(11), 5740–5752. 10.1074/jbc.M115.679126 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eskuri JM, Stanley CM, Moore SA, & Mathews KD (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, 17(1), 132–134. 10.1111/j.1529-8027.2012.00370.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Farwell KD, Shahmirzadi L, El-Khechen D, Powis Z, Chao EC, Tippin Davis B, Baxter RM, Zeng W, Mroske C, Parra MC, Gandomi SK, Lu I, Li X, Lu H, Lu H-M, Salvador D, Ruble D, Lao M, Fischbach S, … Tang S (2015). Enhanced utility of family-centered diagnostic exome sequencing with Inheritance model–based analysis: Results from 500 unselected families with undiagnosed genetic conditions. Genetics in Medicine, 17(7), 578–586. 10.1038/gim.2014.154 [DOI] [PubMed] [Google Scholar]
  9. Forrester N, Rattihalli R, Horvath R, Maggi L, Manzur A, Fuller G, Gutowski N, Rankin J, Dick D, Buxton C, Greenslade M, & Majumdar A (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, 7(2), 137–143. 10.3233/JND-200472 [DOI] [PubMed] [Google Scholar]
  10. Grice SJ, Sleigh JN, Motley WW, Liu JL, Burgess RW, Talbot K, & Cader MZ (2015). Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology. Human Molecular Genetics, 24(15), 4397–4406. 10.1093/hmg/ddv176 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Griffin LB, Sakaguchi R, Mcguigan D, Gonzalez MA, Searby C, Züchner S, Hou YM, & Antonellis A (2014). Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations. Human Mutation, 35(11), 1363–1371. 10.1002/humu.22681 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, & Yang XL (2015). CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature, 526(7575), 710–714. 10.1038/nature15510 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. James PA, Cader MZ, Muntoni F, Childs AM, Crow YJ, & Talbot K (2006). Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene. Neurology, 67(9), 1710–1712. 10.1212/01.wnl.0000242619.52335.bc [DOI] [PubMed] [Google Scholar]
  14. Kawakami N, Komatsu K, Yamashita H, Uemura K, Oka N, Takashima H, & Takahashi R (2014). A novel mutation in glycyl-tRNA synthetase caused Charcot–Marie–Tooth disease type 2D with facial and respiratory muscle involvement. Clinical Neurology, 54(11), 911–915. 10.5692/clinicalneurol.54.911 [DOI] [PubMed] [Google Scholar]
  15. Lee DC, Meyer-Schuman R, Bacon C, Shy ME, Antonellis A, & Scherer SS (2019). A recurrent GARS mutation causes distal hereditary motor neuropathy. Journal of the Peripheral Nervous System, 24(4), 320–323. 10.1111/jns.12353 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lee HJ, Park J, Nakhro K, Park JM, Hur YM, Choi BO, & Chung KW (2012). Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type v. Journal of the Peripheral Nervous System, 17(4), 418–421. 10.1111/j.1529-8027.2012.00442.x [DOI] [PubMed] [Google Scholar]
  17. Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, & Lee YC (2015). Two novel de novo GARS mutations cause early-onset axonal Charcot–Marie–Tooth disease. PLoS ONE, 10(8), e0133423. 10.1371/journal.pone.0133423 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Markovitz R, Ghosh R, Kuo ME, Hong W, Lim J, Bernes S, Manberg S, Crosby K, Tanpaiboon P, Bharucha-Goebel D, Bonnemann C, Mohila CA, Mizerik E, Woodbury S, Bi W, Lotze T, Antonellis A, Xiao R, & Potocki L (2020). GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment. American Journal of Medical Genetics, Part A, 182(5), 1167–1176. 10.1002/ajmg.a.61544 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mendonsa S, von Kuegelgen N, Bujanic L, & Chekulaeva M (2021). Charcot–Marie–Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response. Nucleic Acids Research, 49(17), 10007–10017. 10.1093/nar/gkab730 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meyer-Schuman R, & Antonellis A (2017). Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Human Molecular Genetics, 26(R2), R114–R127. 10.1093/hmg/ddx231 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, & Antonellis A (2017). Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Human Mutation, 38(10), 1412–1420. 10.1002/humu.23287 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Qin X, Hao Z, Tian Q, Zhang Z, Zhou C, & Xie W (2014). Cocrystal structures of glycyl-tRNA synthetase in complex with tRNA suggest multiple conformational states in glycylation. Journal of Biological Chemistry, 289(29), 20359–20369. 10.1074/jbc.M114.557249 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Spaulding EL, Hines TJ, Bais P, Tadenev A, Schneider R, Jewett D, Pattavina B, Pratt SL, Morelli KH, Stum MG, Hill DP, Gobet C, Pipis M, Reilly MM, Jennings MJ, Horvath R, Bai Y, Shy ME, Alvarez-Castelao B, … Burgess RW (2021). The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science, 373(6559), 1156–1161. 10.1126/science.abb3414 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Vitkup D, Sander C, & Church GM (2003). The amino-acid mutational spectrum of human genetic disease. Genome Biology, 4(11), R72. 10.1186/gb-2003-4-11-r72 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yalcouyé A, Diallo SH, Coulibaly T, Cissé L, Diallo S, Samassékou O, Diarra S, Coulibaly D, Keita M, Guinto CO, Fischbeck K, & Landouré G (2019). A novel mutation in the GARS gene in a Malian family with Charcot–Marie–Tooth disease. Molecular Genetics and Genomic Medicine, 7(7), e00782. 10.1002/mgg3.782 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material
NIHMS1817157-supplement-Supplementary_material.docx (22.5KB, docx)

Data Availability Statement

Additional clinical data or findings are available from the authors upon reasonable request. The GARS1 p.Pro336Arg variant has been submitted to ClinVar, accession number VCV001067545.2 (https://www.ncbi.nlm.nih.gov/clinvar/). The GARS1 p.Pro336His has been submitted to ClinVar, submission identification number SUB11111758 (https://www.ncbi.nlm.nih.gov/clinvar/).

RESOURCES