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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

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.
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pone.0133423.g001: 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.

Mentions: The average coverage and read depth of the target GARS sequence are 98% and 516.4X per targeted base, respectively. Mutational analyses of GARS in the 54 unrelated patients with CMT2 revealed three heterozygous missense variants, including p.Asp146Tyr (c.598G>T), p.Met238Arg (c.875T>G) (Fig 1A) and p.Asn208Asp (c.784A>G). The last variant was likely a benign polymorphism, as it was absent in two affected siblings of the proband. However, the first two variants, p.Asp146Tyr and p.Met238Arg, are de novo mutations (Fig 1B) and are absent in the 61,486 ethnically diverse individuals (122,972 chromosomes) in ExAC, which includes approximately 4,300 individuals from East Asian populations. These mutations are also absent from dbSNP and the 1,000 ethnically matched control chromosomes. Both variants are predicted to be disease-causing mutations by CADD and Mutation Taster programs. The CADD v1.2 PHRED scores for both chr7:30642678G>T and chr7:30649340T>G are 33.0, which place GARS p.Asp146Tyr and p.Met238Arg in the top 0.05% most deleterious variants in the genome [25]. Mutation Taster predicted both variants to be disease-causing with strong probability values larger than 0.99; a probability value close to 1 indicates a high “security” of the prediction [26]. The 146th and 238th amino acid residues of the human cytoplasmic GlyRS protein, which is encoded by GARS, are also highly evolutionarily conserved (Fig 1C).


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526224&req=5

pone.0133423.g001: 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.
Mentions: The average coverage and read depth of the target GARS sequence are 98% and 516.4X per targeted base, respectively. Mutational analyses of GARS in the 54 unrelated patients with CMT2 revealed three heterozygous missense variants, including p.Asp146Tyr (c.598G>T), p.Met238Arg (c.875T>G) (Fig 1A) and p.Asn208Asp (c.784A>G). The last variant was likely a benign polymorphism, as it was absent in two affected siblings of the proband. However, the first two variants, p.Asp146Tyr and p.Met238Arg, are de novo mutations (Fig 1B) and are absent in the 61,486 ethnically diverse individuals (122,972 chromosomes) in ExAC, which includes approximately 4,300 individuals from East Asian populations. These mutations are also absent from dbSNP and the 1,000 ethnically matched control chromosomes. Both variants are predicted to be disease-causing mutations by CADD and Mutation Taster programs. The CADD v1.2 PHRED scores for both chr7:30642678G>T and chr7:30649340T>G are 33.0, which place GARS p.Asp146Tyr and p.Met238Arg in the top 0.05% most deleterious variants in the genome [25]. Mutation Taster predicted both variants to be disease-causing with strong probability values larger than 0.99; a probability value close to 1 indicates a high “security” of the prediction [26]. The 146th and 238th amino acid residues of the human cytoplasmic GlyRS protein, which is encoded by GARS, are also highly evolutionarily conserved (Fig 1C).

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