The GARS gene is rarely mutated in Japanese patients with Charcot–Marie–Tooth neuropathy

Abe, Akiko; Hayasaka, Kiyoshi

doi:10.1038/jhg.2009.25

Cited by 22 publications

(17 citation statements)

References 14 publications

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“…GARS or GDAP1 mutations are very rare and were detected in one patient each. 33 No disease-causing mutation was identified in B80% of patients with axonal CMT. An unknown cause in axonal CMT is more frequent than that in demyelinating CMT.…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.

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Section: Discussionmentioning

confidence: 99%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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“…Of the 13 CMT-linked mutations on GlyRS (from patients and mice) identified so far (Fig. 1A), two-C201R from ENU-induced mice (corresponding to C157R in the human sequence) and P244L from a Japanese patient-were published recently (10,13). Before carrying out the conformational studies in solution, we determined that the two newly identified CMTassociated residues P244 and C157, like the other 11, were localized near the dimer interface (Fig.…”

Section: Dimer Interface Localization Of Two Newly Identified Cmt-assmentioning

confidence: 99%

Dispersed disease-causing neomorphic mutations on a single protein promote the same localized conformational opening

Zhang

Chong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The question of how dispersed mutations in one protein engender the same gain-of-function phenotype is of great interest. Here we focus on mutations in glycyl-tRNA synthetase (GlyRS) that cause an axonal form of Charcot-Marie-Tooth (CMT) diseases, the most common hereditary peripheral neuropathies. Because the disease phenotype is dominant, and not correlated with defects in the role of GlyRS in protein synthesis, the mutant proteins are considered to be neomorphs that gain new functions from altered protein structure. Given that previous crystal structures showed little conformational difference between dimeric wild-type and CMT-causing mutant GlyRSs, the mutant proteins were investigated in solution by hydrogen-deuterium exchange (monitored by mass spectrometry) and small-angle X-ray scattering to uncover structural changes that could be suppressed by crystal packing interactions. Significantly, each of five spatially dispersed mutations induced the same conformational opening of a consensus area that is mostly buried in the wild-type protein. The identified neomorphic surface is thus a candidate for making CMT-associated pathological interactions, and a target for disease correction. Additional result showed that a helix-turn-helix WHEP domain that was appended to GlyRS in metazoans can regulate the neomorphic structural change, and that the gain of function of the CMT mutants might be due to the loss of function of the WHEP domain as a regulator.Overall, the results demonstrate how spatially dispersed and seemingly unrelated mutations can perpetrate the same localized effect on a protein.aminoacyl tRNA synthetase | hereditary motor and sensory neuropathy | dimer formation

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“…We describe clinical findings of a Japanese patient with CMT2D with a novel mutation of the GARS. The gene mutation of this patient has been reported in a recent genetic study on CMT neuropathies in Japan [2].A 10-year-old boy with normal birth and development who could not run fast from his early childhood noticed weakness of the fingers. On admission at the age of 15, he showed atrophy in the bilateral thenar, hypothenar, dorsal interossei and tibialis anterior muscles (Fig.…”

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Charcot–Marie–Tooth disease type 2D with a novel glycyl-tRNA synthetase gene (GARS) mutation

et al. 2010

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Sirs,Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are autosomal dominant neuropathy/neuronopathy associated with heterozygous mutations in the glycyl-tRNA synthetase (GlyRS) gene (GARS), characterized by weakness and atrophy that primarily affects the upper extremities [1]. We describe clinical findings of a Japanese patient with CMT2D with a novel mutation of the GARS. The gene mutation of this patient has been reported in a recent genetic study on CMT neuropathies in Japan [2].A 10-year-old boy with normal birth and development who could not run fast from his early childhood noticed weakness of the fingers. On admission at the age of 15, he showed atrophy in the bilateral thenar, hypothenar, dorsal interossei and tibialis anterior muscles (Fig. 1a), grade 2 weakness of the tibialis anterior, peroneus longus, and extensor muscles of toes, and grade 4 weakness of the dorsal interossei, thenar, hypothenar, extensor muscles of fingers and tibialis posterior bilaterally, while the gastrocnemius muscles were spared. Pes cavus was not present.Deep tendon reflexes were diminished in all the extremities. There was glove-and stocking-type sensory disturbance for touch, pain and temperature, while the deep sensation was spared. He showed steppage gait. Serum concentrations of creatinine kinase [927 IU/L (normal \ 306)] were elevated. CSF was normal.

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The GARS gene is rarely mutated in Japanese patients with Charcot–Marie–Tooth neuropathy

Cited by 22 publications

References 14 publications

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Dispersed disease-causing neomorphic mutations on a single protein promote the same localized conformational opening

Charcot–Marie–Tooth disease type 2D with a novel glycyl-tRNA synthetase gene (GARS) mutation

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