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

Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC - PLoS ONE (2015)

Bottom Line: The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0133423.g003: 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.

Mentions: The pathogenic effects of these two mutations appear to be related to their roles in the protein conformational dynamics and homodimeric protein-protein interactions of human GlyRSs. On the basis of the three-dimensional structure of the human GlyRS dimer, Asp146 is located within the insertion I domain and Met238 is situated in the catalytic domain and also at the dimer interface (Fig 3) [10]. Insertion I domain is involved in multiple conformational changes in GlyRS during catalysis, and an altered GlyRS dimer interface has been recognized as a common feature of previously identified CMT-associated GlyRS mutants [10, 11, 28]. Therefore, GARS p.Asp146Tyr and p.Met238Arg mutations might cause CMT by compromising the enzymatic function of human GlyRS and influencing its functional conformations or disrupting the dimer interface.


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

Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526224&req=5

pone.0133423.g003: 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.
Mentions: The pathogenic effects of these two mutations appear to be related to their roles in the protein conformational dynamics and homodimeric protein-protein interactions of human GlyRSs. On the basis of the three-dimensional structure of the human GlyRS dimer, Asp146 is located within the insertion I domain and Met238 is situated in the catalytic domain and also at the dimer interface (Fig 3) [10]. Insertion I domain is involved in multiple conformational changes in GlyRS during catalysis, and an altered GlyRS dimer interface has been recognized as a common feature of previously identified CMT-associated GlyRS mutants [10, 11, 28]. Therefore, GARS p.Asp146Tyr and p.Met238Arg mutations might cause CMT by compromising the enzymatic function of human GlyRS and influencing its functional conformations or disrupting the dimer interface.

Bottom Line: The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus