title: Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy.
abstract: Dominant-intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral motor and sensory neurons. Three dominant mutations in the YARS gene, encoding tyrosyl-tRNA synthetase (TyrRS), have so far been associated with DI-CMT type C. The molecular mechanisms through which mutations in YARS lead to peripheral neuropathy are currently unknown, and animal models for DI-CMTC are not yet available. Here, we report the generation of a Drosophila model of DI-CMTC: expression of the 3 mutant--but not wild type--TyrRS in Drosophila recapitulates several hallmarks of the human disease, including a progressive deficit in motor performance, electrophysiological evidence of neuronal dysfunction and morphological signs of axonal degeneration. Not only ubiquitous, but also neuron-specific expression of mutant TyrRS, induces these phenotypes, indicating that the mutant enzyme has cell-autonomous effects in neurons. Furthermore, biochemical and genetic complementation experiments revealed that loss of enzymatic activity is not a common feature of DI-CMTC-associated mutations. Thus, the DI-CMTC phenotype is not due to haploinsufficiency of aminoacylation activity, but most likely to a gain-of-function alteration of the mutant TyrRS or interference with an unknown function of the WT protein. Our results also suggest that the molecular pathways leading to mutant TyrRS-associated neurodegeneration are conserved from flies to humans.
authors: Laboratory of Developmental Genetics, Center for Human Genetics, Children's Hospital, University of Leuven, BE-3000 Leuven, Belgium.
authors: Erik
authors: E
authors: Storkebaum
authors: Ricardo
authors: R
authors: Leitão-Gonçalves
authors: Tanja
authors: T
authors: Godenschwege
authors: Leslie
authors: L
authors: Nangle
authors: Monica
authors: M
authors: Mejia
authors: Inge
authors: I
authors: Bosmans
authors: Tinne
authors: T
authors: Ooms
authors: An
authors: A
authors: Jacobs
authors: Patrick
authors: P
authors: Van Dijck
authors: Xiang-Lei
authors: XL
authors: Yang
authors: Paul
authors: P
authors: Schimmel
authors: Koen
authors: K
authors: Norga
authors: Vincent
authors: V
authors: Timmerman
authors: Patrick
authors: P
authors: Callaerts
authors: Albena
authors: A
authors: Jordanova
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004594:Electrophysiology; D005799:Genes, Dominant; D008156:Luciferases; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*
chemical_list: D008156:Luciferases; D014448:Tyrosine-tRNA Ligase