Disease relevance of Dst

• Two bullous pemphigoid antigens, BPAG1 and BPAG2, have been recently cloned and mapped to human chromosomes 6p12-p11 and 10q24.3, respectively [1].
• Dystonia musculorum (dt) is a hereditary neurodegenerative disease in mice that leads to a sensory ataxia [2].
• 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 [3].
• Dystonia musculorum (dt) is an inherited neurodegenerative disorder in mice [4].
• 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 [3].

Psychiatry related information on Dst

• Dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar tracts, were impaired in terms of horizontal and vertical motor activity, hole poking, exploration, and motor coordination [5].

High impact information on Dst

• Sensory neurodegeneration occurs in mice defective in BPAG1, a gene encoding cytoskeletal linker proteins capable of anchoring neuronal intermediate filaments to actin cytoskeleton [6].
• This interaction is functionally important; in mice and in vitro, neurons lacking BPAG1 display short, disorganized, and unstable microtubules defective in axonal transport [6].
• Typified by rapid degeneration of sensory neurons, dystonia musculorum mice have a defective BPAG1 gene, known to be expressed in epidermis [7].
• 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 [7].
• BPAG1 is the major antigenic determinant of autoimmune sera of bullous pemphigoid (BP) patients [8].

Chemical compound and disease context of Dst

• Characterization of components of this protein mixture was undertaken using human autoantibodies from bullous pemphigoid (BP) patients that have been shown to recognize hemidesmosomal plaque elements (Mutasim, D. F., Y. Takahashi, R. S. Labib, G. J. Anhalt, H. P. Patel, and L. A. Diaz. 1985. J. Invest. Dermatol. 84:47-53) and by production of mAbs [9].
• We report here studies to determine the fate of the hemidesmosome components, alpha 6 beta 4 integrin and the bullous pemphigoid antigens (BPAGs), as recognized by bullous pemphigoid autoantisera (BPA), in migrating epithelium [10].
• The time courses (0.5, 2.0, 4.0 and 48.0 h) of boron concentrations in melanoma, normal skin, and blood were determined in male Syrian (golden) hamsters bearing Greene's melanomas following a single intraperitoneal injection of either p-, m- or o-BPA (100 mg/kg of BPA fructose in 1.0 ml of saline) [11].

Biological context of Dst

• The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles [12].
• Only Va and dt appear to be associated with some deficiency in DNA repair [13].
• Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration [8].
• We describe here a line of mice in which an hsp68-lacZ transgene is expressed in unstressed developing neural tissue and where the transgene insertion has caused a mutation of a neural tissue-specific gene, dystonia musculorum (dt) [14].
• This direct correlation of genotype and phenotype indicates that the dt mutation acts via a mechanism intrinsic to affected neurons [15].

Anatomical context of Dst

• Mutations in BPAG1 cause sensory neuron degeneration and skin fragility in mice [12].
• The intermediate filament protein peripherin is the specific interaction partner of mouse BPAG1-n (dystonin) in neurons [16].
• 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 [16].
• 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 [16].
• When the inner dental epithelium differentiates, a decrease of E-cadherin, plakoglobin, and BP-230 is seen [17].

Associations of Dst with chemical compounds

• Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties [12].
• Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum [18].
• Trehalose conserves expression of bullous pemphigoid antigen 180 during desiccation and freezing [19].
• The binding sites of four other lectins, WGA, MPA, Con A and BPA, remained expressed during the course of development, being indicative for the carbohydrate side-chains beta-GlcNAc(1-4)Gluc, alpha-Gal(1-3)GalNAc, alpha-D-Man/alpha-D-Gluc and alpha-GalNAc [20].
• Bisphenol A [2, 2 bis (4-hydoxyphenyl) propane; BPA] is a widely used endocrine disruptors and has estrogenic activities [21].

Physical interactions of Dst

• 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 [16].
• Sequence analysis revealed extended homology of mACF7 with both the actin binding domain (ABD) and the Bpag1 portions of dystonin [22].

Co-localisations of Dst

• Here we extend previous studies to report that by immunofluorescence microscopy the alpha 6 integrin subunit colocalizes with bullous pemphigoid antigen and type VII collagen in newly forming hemidesmosomes in the developing 17-day fetal rabbit eye [23].

Regulatory relationships of Dst

• By combining in vivo electroporation with organotypic cultures, we show that an already identified BPAG1 enhancer/promoter is differentially regulated by homeoproteins Hoxc-8 and Engrailed in the embryonic spinal cord and mesencephalon [24].

Other interactions of Dst

• Moreover, mACF7 and Dst display similar isoform diversity and encode similar sized transcripts in the nervous system [22].
• Several proteins belonging to the plakin family of cytoskeletal linker proteins have recently been identified, including dystonin/Bpag1 and plectin [25].
• Autoantibodies in BP react with BP180 and BP230, two major components of the hemidesmosome, a cell structure involved in dermal-epidermal adhesion [26].
• Together, these findings demonstrate that the early phases of myogenic differentiation occur independently of Bpag1 [27].
• These findings suggested that stimulation of prolactin production by estrogenic effects of BPA would affect cytokine profiles, and lead to imbalanced cellular immune response [21].

Analytical, diagnostic and therapeutic context of Dst

• Functional defects in these cell types could account for the dystonic symptoms of dt mice not explained by simple sensory denervation [4].
• To determine the impact of the known and unknown mutations on transcript levels, RT-PCR was performed to detect various coding regions of the dystonin/Bpag1 transcripts in brain and muscle from multiple dt alleles: dt(Tg4), dt(Alb), dt(24J), dt(27J), and dt(Frk) [28].
• We have examined expression of mouse Macf2, encoding macrophin-2, in adult tissues and in the developing, neonatal, and mature inner ear by in situ hybridization [29].
• Northern blot analysis identified three large tissue-specific Macf2 transcripts: a 16-kb mRNA in skeletal muscle and heart, a 15-kb mRNA in brain, and a 9-kb mRNA in RNA from ovary plus uterus [29].
• Analysis of antigens recognized by autoantibodies in herpes gestationis. Usefulness of immunoblotting using a fusion protein representing an extracellular domain of the 180 kD bullous pemphigoid antigen [30].

References