An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy
| Autor: | Robert W. Burgess, Martin Koltzenburg, Linda Greensmith, Ruth Chia, Sebastian Brandner, Hazel P. Williams, Rachel Kendall, Francesca Achilli, Patrick M. Nolan, Virginie Bros-Facer, Jan van Minnen, M Groves, Valter Tucci, Gareth Banks, Joanne E. Martin, Carole D. Nickols, Kevin Talbot, Elizabeth M. C. Fisher, M Z Cader, M AlQatari, Kevin L. Seburn |
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| Rok vydání: | 2009 |
| Předmět: |
Glycine-tRNA Ligase
Male medicine.medical_specialty Sensory Receptor Cells Molecular Sequence Data Neuroscience (miscellaneous) Medicine (miscellaneous) Gene mutation Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Glycine—tRNA ligase 03 medical and health sciences Mice 0302 clinical medicine Immunology and Microbiology (miscellaneous) Charcot-Marie-Tooth Disease Internal medicine medicine Animals Humans Amino Acid Sequence Axon 030304 developmental biology Genetics Motor Neurons 0303 health sciences Mutation Mice Inbred BALB C Mice Inbred C3H Sequence Homology Amino Acid Spinal muscular atrophy medicine.disease Disease Models Animal Peripheral neuropathy Endocrinology medicine.anatomical_structure Phenotype Peripheral nervous system Ethylnitrosourea Female Neuron 030217 neurology & neurosurgery Research Article |
| Zdroj: | Disease modelsmechanisms. 2(7-8) |
| ISSN: | 1754-8411 |
| Popis: | SUMMARY Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, GarsC201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The GarsC201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons. |
| Databáze: | OpenAIRE |
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