Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity

Thomas, P. K.; Calne, D. B.

doi:10.1136/jnnp.37.1.68

Cited by 87 publications

(30 citation statements)

References 19 publications

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“…CMT is usually caused by inherited or de novo mutations in genes related to the structures and functions of myelin sheath or axon (24). Based on the nerve conduction velocity, CMT can be roughly divided into the CMT1 subtype with demyelinating and reduced nerve conduction velocities, the CMT2 subtype with axonal and moderately reduced or normal nerve conduction velocities, and the intermediate subtypes, respectively (25,26). Subtypes are further classified according to the inheritance patterns and gene mutations, and more than 50 genes are implicated in various subtypes (24,27).…”

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confidence: 99%

Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Deng

Qin

Chen

et al. 2016

Journal of Biological Chemistry

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Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great research interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA Gly respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases). Aminoacyl-tRNA synthetases (aaRSs)2 play essential roles in mediating genetic information transfer from mRNAs to proteins and attach amino acids to their cognate tRNA molecules in a two-step reaction. In the first step of the reaction, the enzymes catalyze the condensation between ATP and the specific amino acid to generate an aminoacyl-adenylate intermediate. In the second, they transfer the activated amino acid to the acceptor stem of cognate tRNA to form the product aminoacyl-tRNA. The 20 aaRSs can be grouped into two distinct classes based of the conservation of primary sequences and quaternary structures (1-7). Glycyl-tRNA synthetase (GlyRS) is a class II enzyme and possesses three conserved signature motifs at the active site. However, different from other aaRSs, the quaternary structures of GlyRSs are not conserved phylogenetically. Two oligomeric forms have been discovered in nature: whereas eukaryotic and archaeal GlyRSs form ␣2 homodimers and belong to subclass IIa, their eubacterial counterparts form ␣2␤2 heterotetramers and belong to subclass . No significant sequence homology can be found between the two subtypes. In addition to the sequence and structure diversity, studies also show that GlyRSs only aminoacylate tRNA molecules within their own kingdoms, and crossspecies glycylation is rare. This phenomenon may be attributed to the distinct discriminator base at position 73. In eukaryotes, it is an adenosine that precedes the 3Ј-CCA end, whereas in prokaryotes, a uridine is present (9,11,14,15). Therefore, the tRNA recognition mode is an interesting problem, but it is poorly understood.The human GlyRS (hGlyRS) is a class IIa synthetase and forms a homodimer using motif 1. Motifs 2 and 3, on the other hand, are responsible for recognizing the substrates glycine and ATP. Additionally, hGlyRS features an N-terminal WHEP-TRS domain, as well as several insertion domains named insertions 1-3 (9, 16), most of which are flexible in structure (17). Recent studies have shown that aaRSs have developed functions other than aminoacyl...

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confidence: 99%

Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Deng

Qin

Chen

et al. 2016

Journal of Biological Chemistry

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“…Conversely, patients with MNCV higher than 38 m/s but with a decrease in compound muscle action potential amplitudes are considered to be affected by axonal CMT. A third, less-defined subtype of the disease called intermediate CMT is characterized by MNCV values between 38 and 45 m/s (some authors report a larger interval: 25-35 to 45 m/s) [Thomas and Calne, 1974;Bouche et al, 1983;Rossi et al, 1985;Verhoeven et al, 2001;Patzko and Shy, 2011].…”

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Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

Azzedine

Senderek²,

Rivolta³

et al. 2012

Mol Syndromol

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Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders of the peripheral nervous system, mainly characterized by distal muscle weakness and atrophy leading to motor handicap. With an estimated prevalence of 1 in 2,500, this condition is one of the most commonly inherited neurological disorders. Mutations in more than 30 genes affecting glial and/or neuronal functions have been associated with different forms of CMT leading to a substantial improvement in diagnostics of the disease and in the understanding of implicated pathophysiological mechanisms. However, recent data from systematic genetic screening performed in large cohorts of CMT patients indicated that molecular diagnosis could be established only in ∼50–70% of them, suggesting that additional genes are involved in this disease. In addition to providing an overview of genetic and functional data concerning various CMT forms, this review focuses on recent data generated through the use of highly parallel genetic technologies (SNP chips, sequence capture and next-generation DNA sequencing) in CMT families, and the current and future impact of these technologies on gene discovery and diagnostics of CMTs.

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“…Onze indivíduos com VCN motora menor do que 38 m/s constituíram o tipo I (desmielinizante) e 34 com VCN motora acima de 38 m/s formaram o tipo II (axonal) 27 . Em 18 pacientes pudemos medir a VCN motora do fibular, o que não permitiu classificar a doença de CMT nas duas formas.…”

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Doença de Charcot-Marie-Tooth: estudos eletromiográficos em 45 pacientes

Freitas

Nascimento

Nevares

et al. 1995

Arq. Neuro-Psiquiatr.

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RESUMO -Foi realizada eletroneuromiografia em 45 pacientes com doença de Charcot-Marie-Tooth (CMT). A classificação em tipo I e tipo II da doença de CMT foi feita com base na neurocondução motora do mediano e do ulnar. Assim 11 pacientes eram do tipo I e 34 eram do tipo II. No tipo I não houve relação entre a queda da VCN motora do ulnar e mediano com o quadro clínico da doença. Devido a ausência do potencial de ação sensitivo (PAS) do nervo sural em muitos casos, achamos impossível a classificação da doença pela neurocondução deste nervo. Muitos pacientes com doença de CMT II, tinham neurocondução normal, porém a amplitude do PAS do sural estava ausente ou reduzida, mostrando tratar-se realmente de doença do nervo periférico e não da ponta anterior da medula. Achamos que o estudo da neurocondução é o mais importante na classificação da doença de CMT. PALAVRAS-CHAVE: doença de Charcot-Marie-Tooth, neurocondução, eletromiografia. Charcot-Marie-Tooth disease: electromyographic studies in 45 casesSUMMARY -The electrophysiological studies of 45 patients with Charcot-Marie-Tooth disease (CMT) are presented. The nerve conduction of the motor median and ulnar nerves permitted us to separate our patients in two types: type I (demyelinating) with motor nerve conduction (MNC) below 38 m/s (11 cases) and type II with MNC normal or above 38 m/s (34 cases). In type I there was no correlation between reduction in MNC and clinical severity. It was not possible to classificate the disease on the sural nerve sensory action potential (SAP). They were unobtainable in most cases. In many patients with CMT type II the MNC was normal. In the cases the sural SAP was absent or reduced. We concluded that the MNC study is the best useful test to classify CMT disease in type I and type II.KEY WORDS: Charcot-Marie-Tooth disease, nerve conduction velocity, electromyography.Os estudos elétricos do nervo periférico e do músculo na doença de Charcot-Marie-Tooth (CMT) começaram com Charcot e Marie 5 , em 1886, quando se referiram à inexcitabilidade galvânica e farádica dos músculos nos cinco pacientes por eles descritos. Déjérine e Sottas 7 , em 1893, também relataram a alteração da contratilidade elétrica muscular de seus enfermos. Os dois irmãos referidos por Sachs 24 , em 1890, com doença de CMT tinham diminuição da resposta muscular nos quatro membros aos estímulos pelas correntes farádica e galvânica. Roussy e Levy 24 , em 1926, colocaram a hipoexcitabilidade farádica e galvânica como parte da afecção por eles descrita. Mas, na realidade,

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Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity

Cited by 87 publications

References 19 publications

Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

Doença de Charcot-Marie-Tooth: estudos eletromiográficos em 45 pacientes

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