Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V

Abstract

Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the first example of an aminoacyl tRNA synthetase being implicated in a human genetic disease, which makes genes that encode these enzymes relevant candidates for other inherited neuropathies and motor neuron diseases. Charcot-Marie-Tooth (CMT) disease constitutes a heterogeneous group of peripheral neuropathies estimated to affect 1 in 2,500 individuals (Skre 1974). The clinical features of CMT include muscular weakness and atrophy in the distal extremities, steppage gait, pes cavus, absent or diminished deep-tendon reflexes, and impaired sensation (Murakami et al. 1996). Through the measurement of motor nerve conductance velocities (MNCVs), CMT can be subdivided into two classes (Dyck and Lambert 1968). In CMT1, patients exhibit decreased MNCVs with demyelinating axons. In CMT2, patients exhibit normal MNCVs and no demyelination but have decreased amplitudes of evoked motor and sensory nerve responses. To date, six subtypes of CMT2 have been reported (CMT2A-F), with the genes responsible for

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

“…In addition, we showed that both conditions are genetically heterogeneous, as some individuals with each phenotype do not carry a BSCL2 mutation. Also, the originally described dHMN-V phenotype 12 (also called distal spinal muscular atrophy V and CMT 2D), which has already been associated with mutations in the gene glycyl-tRNA synthetase 13 (GARS; OMIM #600794), supports the presence of genetic heterogeneity. Further genotype-phenotype studies are needed to find out whether the distinct phenotypes correlate with specific mutations and to establish whether there are phenotypically different forms of dHMN-V caused by mutations in BSCL2 versus GARS.…”

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

“…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)(6)(7)(8).…”

Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth neuropathy

“…So far, 3 DI-CMTC-associated mutations have been identified, all located in the catalytic domain of the protein: 2 missense mutations (G41R and E196K) and one 12-bp in-frame deletion that results in the deletion of 4 amino acids in the TyrRS protein (153-156delVKQV). Interestingly, dominant mutations in the gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), cause Charcot-Marie-Tooth disease type 2D (CMT2D) and distal SMA type V in humans and neuropathy phenotype in mice (7,8). Because many of the diseasecausing mutations in GlyRS do not affect the activity for aminoacylation or protein stability (9), and because GARS haploinsufficiency in the mouse does not lead to neuropathy (8), current speculation is that the neurodegenerative phenotype is caused by a gain of pathogenic function of mutant GlyRS, separable from aminoacylation.…”