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  Axonopathy in the central nervous system is the hallmark of mice with a novel intragenic null mutation of dystonin.

Seehusen, F., Kiel, K., Jottini, S., Wohlsein, P., Habierski, H., Seibel, K., et al. (2016). Axonopathy in the central nervous system is the hallmark of mice with a novel intragenic null mutation of dystonin. Genetics, 204(1), 191-203. doi:10.1534/genetics.116.186932.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-5984-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-87E5-2
Genre: Journal Article

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 Creators:
Seehusen, F., Author
Kiel, K.1, Author              
Jottini, S., Author
Wohlsein, P., Author
Habierski, H., Author
Seibel, K2, Author              
Vogel, T., Author
Urlaub, H.3, Author              
Kollmar, M.4, Author              
Baumgärtner, W., Author
Teichmann, U.1, Author              
Affiliations:
1Animal Facility, MPI for Biophysical Chemistry, Max Planck Society, ou_2355695              
2Department of Cellular Logistics, Max Planck Institute for biophysical chemistry, Max Planck Society, ou_578574              
3Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
4Research Group of Systems Biology of Motor Proteins, MPI for biophysical chemistry, Max Planck Society, ou_578570              

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Free keywords: Axonopathy; Dystonia musculorum; Dystonin deficiency; Genomic deletion; Spontaneous mutation
 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.

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Language(s): eng - English
 Dates: 2016-07-06
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1534/genetics.116.186932
 Degree: -

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Title: Genetics
Source Genre: Journal
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Pages: - Volume / Issue: 204 (1) Sequence Number: - Start / End Page: 191 - 203 Identifier: -