Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease

Abstract

Background: Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive.

Methodology and principal findings: Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.

Conclusion: GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

Fig 1. Two novel de novo GARS mutations.

(A) The novel GARS mutations identified in this study, p.Asp146Tyr and p.Met238Arg, with the sense strand electropherogram shown on the top and a limited reading frame depicting the corresponding amino acid substitutions shown below. (B) Pedigrees of the 2 patients harboring the novel GARS mutations. The arrows indicate the probands. “M” represents the GARS mutations and “W” means wild type. (C) The GARS p.Asp146Tyr and p.Met238Arg mutations reside in an evolutionarily conserved region, as shown by aligning the amino acid sequences of glycyl-tRNA synthetase protein (GlyRS) orthologs from various species.

Fig 2. Clinical features of the patient harboring the GARS p.Asp146Tyr mutation.

(A) Severe weakness and atrophy of the muscles in the feet and legs, pes planus and (B, C) severe intrinsic hand muscle atrophy with claw hand deformity.

Fig 3. The crystal structure of human glycyl-tRNA synthetase (GlyRS) (PDB ID: 2PME).

(A) Mapping of the two GARS mutation sites (p.Asp146Tyr and p.Met238Arg) on one subunit of the human GlyRS dimer. (B) A view of the human GlyRS dimers demonstrating that Met238 is located on the interface between the two subunits. Catalytic, Insertion I and Insertion II domains are colored as indicated.