title: Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin.
abstract: Dystonia musculorum is a neurodegenerative disorder caused by a mutation in the dystonin gene. It has been described in mice and humans where it is called hereditary sensory autonomic neuropathy. Mutated mice show severe movement disorders and die at the age of 3-4 weeks. This study describes the discovery and molecular, clinical, as well as pathological characterization of a new spontaneously occurring mutation in the dystonin gene in C57BL/6N mice. The mutation represents a 40-kb intragenic deletion allele of the dystonin gene on chromosome 1 with exactly defined deletion borders. It was demonstrated by Western blot, mass spectrometry, and immunohistology that mice with a homozygous mutation were entirely devoid of the dystonin protein. Pathomorphological lesions were restricted to the brain stem and spinal cord and consisted of swollen, argyrophilic axons and dilated myelin sheaths in the white matter and, less frequently, total chromatolysis of neurons in the gray matter. Axonal damage was detected by amyloid precursor protein and nonphosphorylated neurofilament immunohistology. Axonopathy in the central nervous system (CNS) represents the hallmark of this disease. Mice with the dystonin mutation also showed suppurative inflammation in the respiratory tract, presumably due to brain stem lesion-associated food aspiration, whereas skeletal muscles showed no pathomorphological changes. This study describes a novel mutation in the dystonin gene in mice leading to axonopathy in the CNS. In further studies, this model may provide new insights into the pathogenesis of neurodegenerative diseases and may elucidate the complex interactions of dystonin with various other cellular proteins especially in the CNS.
authors.affiliation: Department of Pathology, University of Veterinary Medicine, D-30559 Hannover, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Seehusen
authors.affiliation: Animal Facility, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kiel
authors.affiliation: Department of Pathology, University of Veterinary Medicine, D-30559 Hannover, Germany Department of Animal Health, Pathology Unit, Faculty of Veterinary Medicine, University of Parma, I-43100, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Jottini
authors.affiliation: Department of Pathology, University of Veterinary Medicine, D-30559 Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wohlsein
authors.affiliation: Department of Pathology, University of Veterinary Medicine, D-30559 Hannover, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Habierski
authors.affiliation: Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Seibel
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, D-79104, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Vogel
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany Bioanalytics, Department of Clinical Chemistry, University Medical Center Göttingen, D-37075, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Department of NMR-Based Structural Biology, Research Group Systems Biology of Motor Proteins, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kollmar
authors.affiliation: Department of Pathology, University of Veterinary Medicine, D-30559 Hannover, Germany Center for Systems Neuroscience, University of Veterinary Medicine, D-30559 Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Animal Facility, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany ulrike.teichmann@mpibpc.mpg.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Teichmann
mesh_terms: D000483:Alleles; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071821:Dystonin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
chemical_list: D000071821:Dystonin; D009419:Nerve Tissue Proteins
keywords: axonopathy; dystonia musculorum; dystonin deficiency; genomic deletion; spontaneous mutation