Molecular characterization of the genetic lesion in Dystonia musculorum (dt-Alb) mice

Goryunov, Dmitry; Adebola, Adijat; Jefferson, Julius J.; Leung, Conrad L.; Messer, Anne; Liem, Ronald K.H.

doi:10.1016/j.brainres.2006.04.068

Cited by 24 publications

(23 citation statements)

References 22 publications

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“…In contrast to other mutant dystonin alleles (Goryunov et al 2007), the deletion of a large genomic area represents a unique feature of the dt-MP allele. The loss of a 40-kb segment of the 400-kb wild-type genomic dystonin locus in the described new mutant allele represents one of the largest deletion alleles of dystonin after spontaneous mutation so far.…”

Section: Discussionmentioning

confidence: 93%

“…Primary antibodies used are as follows: dystonin/BPAG1 (polyclonal, LS-C123425/70642; LifeSpan Biosciences, Seattle, WA; Figure 1 Structure of different murine dystonin isoforms. The structure of the different dystonin isoforms is shown (adapted from Goryunov et al 2007 1:400), b-amyloid precursor protein (monoclonal, MAB348 Merck Millipore, Darmstadt, Germany; 1:800, microwave pretreatment), phosphorylated neurofilaments (monoclonal, SM312; Covance, Emeryville, CA; 1:8000), nonphosphorylated neurofilaments (monoclonal, SM311; Covance; 1:8000, microwave pretreatment), and myelin basic protein (polyclonal, AB980; Merck Millipore; 1:800) according to a standard immunohistological protocol (Seehusen and Baumgärtner 2010).…”

Section: Msmentioning

confidence: 99%

“…The polyclonal antibody AB18024 was used for the Western blots to detect dystonin protein in brain stem tissue [generous gift from Ronald Liem (Goryunov et al 2007)] of a dt-MP animal (genotype dt/dt) and a healthy dt/+ animal as control. The antibody is directed against the plakin domain of the dystonin protein that is present in all isoforms.…”

Section: Protein Expressionmentioning

confidence: 99%

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Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

et al. 2016

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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. KEYWORDS axonopathy; dystonia musculorum; dystonin deficiency; genomic deletion; spontaneous mutation A spontaneously occurring mutant was described in the mouse, in which the gene dystonin was affected (Ledoux 2011). Dystonin (Dst) [human gene name, DST; former name, bullous pemphigoid antigen 1 (BPAG1)] is a large cytoskeletal linker protein and crucial for maintaining cellular structural integrity (Young and Kothary 2008). Recent research in this field concentrates on the role of dystonin in central nervous tissue and neurological diseases, but not, however, on its parallel expression in musculature and skin.Mice with a mutated dystonin gene develop a severe sensory neuropathy called dystonia musculorum (Duchen 1976). Characteristics are a progressive loss of coordination of the limbs (ataxia) and an early death (Kothary et al. 1988;Guo et al. 1995). There are only few reports about patients with mutations of the human dystonin gene (Giorda et al. 2004;Groves et al. 2010;Edvardson et al. 2012).Several dystonin isoforms are generated from one genomic locus of 400 kb. They are expressed in the central nervous system (CNS) (predominant neuronal isoform "a," 617 kDa and "n," 344 kDa), muscles (predominant muscle isoform "b," 834 kDa), and skin (predominant skin isoform "e," 302 kDa) ( Figure 1 Pool et al...

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Section: Discussionmentioning

confidence: 93%

Section: Msmentioning

confidence: 99%

Section: Protein Expressionmentioning

confidence: 99%

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Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

et al. 2016

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Section: Dystonin Is Essential To Neurons-but For What?mentioning

confidence: 99%

“…2) [Guo et al, 1995;Pool et al, 2005;Brown et al, 1995a;Goryunov et al, 2007]. Two of these, the dt Alb and the Bpag1 knockout mice, affect multiple dystonin isoforms, and the dt Alb mutation results in a complete null for neuronal dystonin [Goryunov et al, 2007]. However, the dt J mutant allele does not result in a loss of epithelial dystonin [Guo et al, 1995], and the dt Tg4 allele may affect only neuronal/muscle isoforms which are generated with the isoform 1 or 2 N-terminal-specific sequences (Fig.…”

Section: Dystonin Is Essential To Neurons-but For What?mentioning

confidence: 99%

Dystonin/Bpag1—A link to what?

Young

Kothary

2007

Cell Motil. Cytoskeleton

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The dystonin/Bpag1 cytoskeletal interacting proteins play important roles in maintaining cytoarchitecture integrity in skin and in the neuromuscular system. The most profound phenotype observed in the dystonin mutant dystonia musculorum (dt) mice is a severe movement disorder, attributed in large part to sensory neuron degeneration. The molecular basis for this phenotype is currently not clear, despite several studies indicating possible causes for the pathology in dt

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Value of the Detection of Circulating Antibodies Against BP Antigens in Unaffected Subjects

Grootenboer‐Mignot

Descamps

2010

Arch Dermatol

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Molecular characterization of the genetic lesion in Dystonia musculorum (dt-Alb) mice

Cited by 24 publications

References 22 publications

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

Dystonin/Bpag1—A link to what?

Value of the Detection of Circulating Antibodies Against BP Antigens in Unaffected Subjects

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