title: Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder.
abstract: Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.
authors.affiliation: Center for Molecular Neurobiology, University of Hamburg, D-20246 Hamburg, Germany.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Rünker
authors.forename: Igor
authors.initials: I
authors.lastname: Kobsar
authors.forename: Torsten
authors.initials: T
authors.lastname: Fink
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.forename: Thomas
authors.initials: T
authors.lastname: Tilling
authors.forename: Peggy
authors.initials: P
authors.lastname: Putthoff
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005799:Genes, Dominant; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D018993:Myelin P0 Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009431:Neural Conduction / Q000235:genetics; D010525:Peripheral Nerves / Q000002:abnormalities* / Q000473:pathology* / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018993:Myelin P0 Protein; D012333:RNA, Messenger