A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease

Latour, Philippe; Thauvin‐Robinet, Christel; Baudelet-Méry, Chantal; Soichot, P.; Cusin, Véronica; Faivre, Laurence; Locatelli, Marie-Claire; Mayençon, Martine; Sarcey, Annie; Broussolle, Emmanuel; Camu, William; David, Albert; Rousson, Robert

doi:10.1016/j.ajhg.2009.12.005

Cited by 198 publications

(182 citation statements)

References 18 publications

(33 reference statements)

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“…The p.Gly102Arg mutation affects a conserved residue in an important domain, and segregates with disease in a pedigree with 9 living individuals. This phenotype is different from the p.Arg329His AARS mutation that was first identified in 2 French families 5 and subsequently in an Australian family. 4 All 3 families had a dominantly inherited axonal neuropathy affecting motor and sensory axons.…”

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confidence: 78%

A novel AARS mutation in a family with dominant myeloneuropathy

et al. 2015

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Objective: To determine the genetic cause of neurodegeneration in a family with myeloneuropathy. Methods:We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.Results: All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G.C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.Conclusion: A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes. Charcot-Marie-Tooth disease (CMT) and hereditary motor and sensory neuropathy (HMSN) are alternative names for inherited neuropathies that are not part of more complex syndromes. With an estimated prevalence of 1 in 2,500 persons, CMT/HMSN is one of the commonest neurogenetic diseases and is subdivided according to clinical, electrophysiologic, histologic, and genetic features.1 CMT2/HMSN-II is a dominantly inherited axonal neuropathy, with nerve conduction velocities greater than 38 m/s. Mutations in more than 20 different genes cause autosomal dominant CMT2. With the exception of some MPZ mutations, these mutations are thought to produce a neuropathy through their direct effects in neurons. Mutations in genes that encode aminoacyl-tRNA synthetases (ARS) cause some forms of CMT2. These enzymes charge tRNAs with their cognate amino acids, establishing the genetic code. Mutations in the glycyl-tRNA synthetase (GARS) gene were the first to be described, found in patients with dominant purely motor (hereditary motor neuropathy 5A) or dominant motor predominant (CMT2D) neuropathy. ; and methionyl-tRNA synthetase (MARS) in late-onset, dominant

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confidence: 78%

A novel AARS mutation in a family with dominant myeloneuropathy

et al. 2015

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“…All mutations associated with CMT2D and neuropathy in humans and mice are in the common, downstream domains of the GARS protein that are shared by both isoforms. For most other tRNA synthetases, separate nuclear genes encode the mitochondrial and cytosolic enzymes and overall the genetics of tRNA synthetase-associated CMTs (Tolkunova et al, 2000;Scheper et al, 2007;Isohanni et al, 2010;Latour et al, 2010;McLaughlin et al, 2010;Vester et al, 2013) does not clearly indicate a mitochondrial basis for the neuropathies. Nonetheless, mitochondrial dysfunction, whether primary or secondary, also cannot be ruled out as contributing to the synaptic dysfunction we observed.…”

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confidence: 99%

Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot–Marie–Tooth Type 2d

et al. 2016

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Patients with Charcot-Marie-Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase (GARS), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D. Quantal analysis of NMJs in two different mouse models of CMT2D (Gars P278KY, Gars C201R ), found synaptic deficits that correlated with disease severity and progressed with age. Results of voltage-clamp studies revealed presynaptic defects characterized by: (1) decreased frequency of spontaneous release without any change in quantal amplitude (miniature endplate current), (2) reduced amplitude of evoked release (endplate current) and quantal content, (3) age-dependent changes in the extent of depression in response to repetitive stimulation, and (4) release failures at some NMJs with high-frequency, long-duration stimulation. Drugs that modify synaptic efficacy were tested to see whether neuromuscular performance improved. The presynaptic action of 3,4 diaminopyridine was not beneficial, whereas postsynaptic-acting physostigmine did improve performance. Smaller mutant NMJs with correspondingly fewer vesicles and partial denervation that eliminates some release sites also contribute to the reduction of release at a proportion of mutant NMJs. Together, these voltage-clamp data suggest that a number of release processes, while essentially intact, likely operate suboptimally at most NMJs of CMT2D mice.

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“…The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5)(6)(7)(8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.…”

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Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.aminoacyl-tRNA synthetase | Charcot-Marie-Tooth disease | distal spinal muscular atrophy type V | neuromuscular disease | neurodevelopment C harcot-Marie-Tooth disease (CMT) is a group of genetically diverse peripheral neuropathies that share the main pathological feature of progressive motor and sensory degeneration (1). Although lifespan is usually unaffected, patients display characteristic muscle weakness and wasting predominantly in the extremities, leading to difficulty walking, foot deformities, and reduced dexterity (2). CMT is traditionally divided into type 1/ demyelinating CMTs that display loss of peripheral nerve myelin causing reduced nerve conduction velocity (NCV), type 2/axonal CMTs typified by axon loss with relatively normal NCVs, and intermediate CMTs that share clinical features of CMT1 and -2 (1). Over 80 different genetic loci have been linked to CMT, which is known to affect ∼1/2,500 people, making it the most common group of hereditary neuromuscular disorders (3).Dominant mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS, are causative of CMT type 2D (CMT2D) [Online Mendelian Inheritance in Man (OMIM) 601472], which normally manifests during adolescence and presents with muscle weakness in the extremities (4). The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5-8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.This housekeeping function of gl...

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A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease

Cited by 198 publications

References 18 publications

A novel AARS mutation in a family with dominant myeloneuropathy

A novel AARS mutation in a family with dominant myeloneuropathy

Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot–Marie–Tooth Type 2d

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

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