Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BPAG1 is the major antigenic determinant of autoimmune sera of bullous pemphigoid (BP) patients. It is made by stratified squamous epithelia, where it localizes to the inner surface of specialized integrin-mediated adherens junctions (hemidesmosomes). To explore the function of BPAG1 and its relation to BP, we targeted the removal of the BPAG1 gene in mice. Hemidesmosomes are otherwise normal, but they lack the inner plate and have no cytoskeleton attached. Though not affecting cell growth or substratum adhesion, this compromises mechanical integrity and influences migration. Unexpectedly, the mice also develop severe dystonia and sensory nerve degeneration typical of dystonia musculorum (dt/dt) mice. We show that in at least one other strain of dt/dt mice, BPAG1 gene is defective.
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PMID:Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. 773 75

Dystonia musculorum (dt) is a hereditary neurodegenerative disease in mice that leads to a sensory ataxia. We have identified and cloned a gene encoded at the dt locus. The product of the dt gene, dystonin, is a neural isoform of a hemidesmosomal protein bullous pemphigoid antigen 1 (bpag1). To investigate the potential role of dystonin in human neuropathies, we have cloned the neural-specific 5' exons of the human DT gene that together with the previously cloned BPAG1 sequences comprise human dystonin. The mouse and human dystonin genes demonstrate the same spectrum of alternatively spliced products, and the amino acid sequences of the neural-specific exons in the mouse and human genes are over 96% identical.
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PMID:Cloning and characterization of the neural isoforms of human dystonin. 857 75

Typified by rapid degeneration of sensory neurons, dystonia musculorum mice have a defective BPAG1 gene, known to be expressed in epidermis. We report a neuronal splice form, BPAG1n, which localizes to sensory axons. Both isoforms have a coiled-coil rod, followed by a carboxy domain that associates with intermediate filaments. However, the amino terminus of BPAG1n differs from BPAG1e in that it contains a functional actin-binding domain. In transfected cells, BPAG1n coaligns neurofilaments and microfilaments, establishing this as a cytoskeletal protein interconnecting actin and intermediate filament cytoskeletons. In BPAG1 null mice, axonal architecture is markedly perturbed, consistent with a failure to tether neurofilaments to the actin cytoskeleton and underscoring the physiological relevance of this protein.
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PMID:An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments. 875 19

Ablation of the BPAG1 gene results in the dystonia musculorum mouse, exhibiting rapid spinal nerve degeneration, dystonic movements, and severe ataxia. By defining the developmental and tissue-specific expression of the neuronal form of BPAG1 (BPAG1-n) and by comparing the corresponding pathology in BPAG1 null mice, we seek here to understand how absence of BPAG1 results in this devastating phenotype in mice and in potentially related human neurological disorders. Throughout normal development, BPAG1-n was expressed in a variety of sensory and autonomic neuronal structures, but was absent or reduced in areas such as basal ganglia that are often affected in dystonias and ataxias. Interestingly, BPAG1-n was also expressed broadly in embryonic motor neurons, but expression declined dramatically after birth. Despite these complex developmental patterns, BPAG1-/- pathology was restricted largely to postnatal development. Moreover, gross neuronal degeneration was restricted to only a few regions where BPAG1-n was found, including dorsal root ganglion neurons and a small subset of motor neurons. Most notably, while skeletal muscle was normal, appearance of severe dystonic ataxia correlated with postnatal degeneration of muscle spindles. Collectively, our findings suggest a mechanism for the BPAG1 null phenotype and indicate that different neurons respond differently to the absence of BPAG1-n, a cytoskeletal linker protein.
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PMID:Developmental expression of BPAG1-n: insights into the spastic ataxia and gross neurologic degeneration in dystonia musculorum mice. 924 12

We report a patient with Shy-Drager syndrome who developed multiple tense blisters mainly on the extremities. Circulating anti-basement membrane zone autoantibodies were detected by the indirect immunofluorescence method. Immunoblot analysis using normal human epidermal extracts demonstrated that this patient's serum reacted only with 230 kD bullous pemphigoid antigen (BPAG1). Concerning the pathoetiology of the association of bullous pemphigoid and Shy-Drager syndrome, we discuss a sequence similarity between BPAG1 and dystonin, a candidate gene for dystonia musculorum.
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PMID:Bullous pemphigoid associated with Shy-Drager syndrome. 971 81

The dystonia musculorum (dt) mouse suffers from severe degeneration of primary sensory neurons. The mutated gene product is named dystonin and is identical to the neuronal isoform of bullous pemphigoid antigen 1 (BPAG1-n). BPAG1-n contains an actin-binding domain at its NH2 terminus and a putative intermediate filament-binding domain at its COOH terminus. Because the degenerating sensory neurons of dt mice display abnormal accumulations of intermediate filaments in the axons, BPAG1-n has been postulated to organize the neuronal cytoskeleton by interacting with both the neurofilament triplet proteins (NFTPs) and microfilaments. In this paper we show by a variety of methods that the COOH-terminal tail domain of mouse BPAG1 interacts specifically with peripherin, but in contrast to a previous study (Yang, Y., J. Dowling, Q.C. Yu, P. Kouklis, D.W. Cleveland, and E. Fuchs. 1996. Cell. 86:655-665), mouse BPAG1 fails to associate with full-length NFTPs. The tail domains interfered with the association of the NFTPs with BPAG1. In dt mice, peripherin is present in axonal swellings of degenerating sensory neurons in the dorsal root ganglia and is downregulated even in other neural regions, which have no obvious signs of pathology. Since peripherin and BPAG1-n also display similar expression patterns in the nervous system, we suggest that peripherin is the specific interaction partner of BPAG1-n in vivo.
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PMID:The intermediate filament protein peripherin is the specific interaction partner of mouse BPAG1-n (dystonin) in neurons. 997 39

BPAG1 (bullous pemphigoid antigen 1) was originally identified as a 230-kDa hemidesmosomal protein and belongs to the plakin family, because it consists of a plakin domain, a coiled-coil rod domain and a COOH-terminal intermediate filament binding domain. To date, alternatively spliced products of BPAG1, BPAG1e, and BPAG1n are known. BPAG1e is expressed in epithelial tissues and localized to hemidesmosomes, on the other hand, BPAG1n is expressed in neural tissues and muscles and has an actin binding domain at the NH(2)-terminal of BPAG1e. BPAG1 is also known as a gene responsible for Dystonia musculorum (dt) neurodegeneration syndrome of the mouse. Another plakin family protein MACF (microtubule actin cross-linking factor) has also an actin binding domain and the plakin domain at the NH(2)-terminal. However, in contrast to its high homology with BPAG1 at the NH(2)-terminal, the COOH-terminal structure of MACF, including a microtubule binding domain, resembles dystrophin rather than plakins. Here, we investigated RNAs and proteins expressed from the BPAG1 locus and suggest novel alternative splicing variants, which include one consisting of the COOH-terminal domain structure homologous to MACF. The results indicate that BPAG1 has three kinds of cytoskeletal binding domains and seems to play an important role in linking the different types of cytoskeletons.
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PMID:Novel alternative splicings of BPAG1 (bullous pemphigoid antigen 1) including the domain structure closely related to MACF (microtubule actin cross-linking factor). 1175 55

The neuronal isoforms of bullous pemphigoid antigen 1 (BPAG1, and also known as dystonin) are a group of large cytoskeletal linker proteins predominantly expressed in sensory neurons. The major neuronal isoforms consist of the spectraplakins (BPAG1/dystonin-a1, -a2, -a3), which have an N-terminus actin-binding domain and a C-terminus microtubule-binding domain. These proteins have crucial roles in cytoskeletal organization and stability, organelle integrity, and intracellular transport. BPAG1 loss-of-function in mice results in a lethal movement disorder known as dystonia musculorum (dt), which is likely caused by rapid sensory neuron degeneration. A human disease termed hereditary and sensory autonomic neuropathy type VI was also identified to be associated with mutations in the BPAG1 gene (DST). This chapter provides an overview of the type of experiments used for analysis of the different isoforms of BPAG1.
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PMID:Functional and Genetic Analysis of Neuronal Isoforms of BPAG1. 2677 67

BPAG1, also known as Dystonin or BP230, belongs to the plakin family of proteins, which has multiple cytoskeleton-binding domains. Several BPAG1 isoforms are produced by a single BPAG1 genomic locus using different promoters and exons. For example, BPAG1a, BPAG1b, and BPAG1e are predominantly expressed in the nervous system, muscle, and skin, respectively. Among BPAG1 isoforms, BPAG1e is well studied because it was first identified as an autoantigen in patients with bullous pemphigoid, an autoimmune skin disease. BPAG1e is a component of hemidesmosomes, the adhesion complexes that promote dermal-epidermal cohesion. In the nervous system, the role of BPAG1a is also well studied because disruption of BPAG1a results in a phenotype identical to that of Dystonia musculorum (dt) mutants, which show progressive motor disorder. However, the expression and function of BPAG1 in muscles is not well studied. The aim of this review is to provide an overview of and highlight some recent findings on the expression and function of BPAG1 in muscles, which can assist future studies designed to delineate the role and regulation of BPAG1 in the dt mouse phenotype and in human hereditary sensory and autonomic neuropathy type 6 (HSAN6).
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PMID:BPAG1 in muscles: Structure and function in skeletal, cardiac and smooth muscle. 2873 6