A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot–Marie–Tooth type 2D in a Chinese family

Sun, Aping; Liu, Xiangyi; Ma, Zheng; Sun, Qingli; Huang, Yu

doi:10.1179/1743132815y.0000000055

Cited by 16 publications

(14 citation statements)

References 16 publications

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“…HMN5A is phenotypically similar to axonal CMT, but without sensory involvement . A series of follow‐up studies reported additional mutations (A57V, D146N, D146Y, S211F, L218Q, M238R, P244L, E279D, I280F, H418R, D500N, G598A), adding up to 16 distinct mutations , distributed throughout the primary GlyRS sequence (Fig. B).…”

Section: Dominant Mutations In Trna Synthetase Genes Cause Charcot‐mamentioning

confidence: 93%

Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation

Storkebaum

2016

BioEssays

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Recent evidence indicates that inhibition of protein translation may be a common pathogenic mechanism for peripheral neuropathy associated with mutant tRNA synthetases (aaRSs). aaRSs are enzymes that ligate amino acids to their cognate tRNA, thus catalyzing the first step of translation. Dominant mutations in five distinct aaRSs cause Charcot‐Marie‐Tooth (CMT) peripheral neuropathy, characterized by length‐dependent degeneration of peripheral motor and sensory axons. Surprisingly, loss of aminoacylation activity is not required for mutant aaRSs to cause CMT. Rather, at least for some mutations, a toxic‐gain‐of‐function mechanism underlies CMT‐aaRS. Interestingly, several mutations in two distinct aaRSs were recently shown to inhibit global protein translation in Drosophila models of CMT‐aaRS, by a mechanism independent of aminoacylation, suggesting inhibition of translation as a common pathogenic mechanism. Future research aimed at elucidating the molecular mechanisms underlying the translation defect induced by CMT‐mutant aaRSs should provide novel insight into the molecular pathogenesis of these incurable diseases.

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Section: Dominant Mutations In Trna Synthetase Genes Cause Charcot‐mamentioning

confidence: 93%

Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation

Storkebaum

2016

BioEssays

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“…The ability of patients with CMT2D to sense vibration is most impaired, followed by light touch, temperature, and pain (20). Furthermore, patients with CMT2D display deficits in deep tendon reflexes of the extremities (22,23), whereas reflexes of patients with dSMA-V remain relatively unperturbed (4,24), implicating defective relay arc afferents rather than efferents. CMT2D sensory defects are dependent on disease severity, but not duration, whereas patients with dSMA-V are refractory to sensory pathogenesis, suggesting that, similar to other neurological diseases (25), the two disorders lie along a spectrum and that diseasemodifying loci may dictate these differences (20).…”

Section: Significancementioning

confidence: 99%

“…A second major conundrum in GlyRS-associated neuropathy is why some patients with dominant GARS mutations and diagnosed with the allelic neuropathy distal spinal muscular atrophy type V (dSMA-V, OMIM 600794) (4), lack the distinguishing mild-tomoderate sensory involvement typical of CMT2D (20)(21)(22)(23). The ability of patients with CMT2D to sense vibration is most impaired, followed by light touch, temperature, and pain (20).…”

Section: Significancementioning

confidence: 99%

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.

135

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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 second major conundrum in GlyRS-associated neuropathy is why some patients with dominant GARS mutations, diagnosed with the allelic neuropathy distal spinal muscular atrophy type V (dSMA-V, OMIM 600794) (4), lack the distinguishing mildto-moderate sensory involvement typical of CMT2D (19)(20)(21)(22). The ability of CMT2D patients to sense vibration is most impaired, followed by light touch, temperature, and pain (19).…”

Section: Introductionmentioning

confidence: 99%

“…The ability of CMT2D patients to sense vibration is most impaired, followed by light touch, temperature, and pain (19). Furthermore, CMT2D patients display deficits in deep tendon reflexes of the extremities (21,22), while reflexes of dSMA-V patients remain relatively unperturbed (4,23), implicating defective relay arc afferents rather than efferents. CMT2D sensory defects are dependent on disease severity not duration, while dSMA-V patients are refractory to sensory pathogenesis, suggesting that the two disorders lie along a spectrum and that disease-modifying loci may dictate these differences (19).…”

Section: Introductionmentioning

confidence: 99%

Sensory neuron fate is developmentally perturbed byGarsmutations causing human neuropathy

Sleigh

Dawes

West

et al. 2016

Preprint

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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 in 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 behaviour 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. This suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments. Significance StatementCharcot-Marie-Tooth disease (CMT) is a collection of genetically diverse inherited nerve disorders with the unifying feature of peripheral neuron degeneration. The mechanisms triggering this motor and sensory nerve dysfunction remain unresolved, as does the reason for the lack of sensory pathology observed in distal hereditary motor neuropathies, which can be associated with CMT genes. To unravel the mechanisms leading to afferent deterioration, we have studied the sensory nervous system of CMT Type 2D mice. Our work indicates that the specific cellular identity of sensory nerves is perturbed in mutant mice pre-natally. CMT therefore manifests through the complex interplay between malfunctioning developmental, maturation, and survival programs, which has important ramifications for therapeutic timing.Keywords: aminoacyl-tRNA synthetase (ARS), Charcot-Marie-Tooth disease (CMT), CMT2D, distal spinal muscular atrophy type V (dSMA-V), dorsal root ganglion (DRG), GARS, glycyl-tRNA synthetase (GlyRS), hereditary motor and sensory neuropathy (HMSN), muscle spindle, neurodevelopment, neuromuscular disease, peripheral neuropathy.

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A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot–Marie–Tooth type 2D in a Chinese family

Abstract: The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population.

Cited by 16 publications

References 16 publications

Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation

Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation

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

Sensory neuron fate is developmentally perturbed byGarsmutations causing human neuropathy

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