title: Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila.
abstract: Charcot-Marie-Tooth disease type 2B (CMT2B) is an inherited axonal peripheral neuropathy. It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement. Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. In the neurons, Rab7 plays a role in the long-range retrograde transport of signalling endosomes in the axons. Here we developed the first animal model of CMT2B, modelling one of the mutations (L129F) in Drosophila melanogaster. Behavioural assays show that this model recapitulates several hallmarks of the human disease. Upon expression of mutant Rab7 in the sensory neurons, larvae present with a reduction of temperature and pain perception. Furthermore, the larvae exhibit a crawling defect when the mutant protein is expressed in the motor neurons. Analysis of axonal transport of Rab7 positive vesicles in sensory neurons of Drosophila larvae and in neurites of mammalian neuroblastoma cells demonstrates that mutant vesicles pause less than their wild-type counterparts. This latter finding indicates that alterations in vesicle transport might contribute to the pathomechanism of CMT2B.
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Department of Medical Genetics, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Katrien
authors: K
authors: Janssens
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Sofie
authors: S
authors: Goethals
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Derek
authors: D
authors: Atkinson
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Biljana
authors: B
authors: Ermanoska
authors: StatUa Center for Statistics, University of Antwerp, B-2000 Antwerpen, Belgium.
authors: Erik
authors: E
authors: Fransen
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Albena
authors: A
authors: Jordanova
authors: Department of Orthopaedics, Medical University Vienna, A-1090 Vienna, Austria.
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium.
authors: Bob
authors: B
authors: Asselbergh
authors: Molecular Genetics Department, VIB, University of Antwerp, B-2610 Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, B-2610 Antwerpen, Belgium. Electronic address: vincent.timmerman@molgen.vib-ua.be.
authors: Vincent
authors: V
authors: Timmerman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology*; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000083083:Laminopathies; D007814:Larva; D008297:Male; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D011984:Sensory Receptor Cells / Q000473:pathology; D014161:Transduction, Genetic; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D029721:Drosophila Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D049452:Green Fluorescent Proteins; D020691:rab GTP-Binding Proteins
keywords: Behavioural assay; Charcot–Marie–Tooth; Drosophila melanogaster; Rab7