-
Molecular Biology of the Cell Feb 2012Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of...
Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of expression of neuronal dystonin isoforms (dystonin-a1/dystonin-a2) is sufficient to cause dt pathogenesis, the diverging function of each isoform and what pathological mechanisms are activated upon their loss remains unclear. Here we show that dt(27) mice manifest ultrastructural defects at the endoplasmic reticulum (ER) in sensory neurons corresponding to in vivo induction of ER stress proteins. ER stress subsequently leads to sensory neurodegeneration through induction of a proapoptotic caspase cascade. dt sensory neurons display neurodegenerative pathologies, including Ca(2+) dyshomeostasis, unfolded protein response (UPR) induction, caspase activation, and apoptosis. Isoform-specific loss-of-function analysis attributes these neurodegenerative pathologies to specific loss of dystonin-a2. Inhibition of either UPR or caspase signaling promotes the viability of cells deficient in dystonin. This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function.
Topics: Animals; Apoptosis; Calcium; Carrier Proteins; Caspases; Cytoskeletal Proteins; Dystonia Musculorum Deformans; Dystonin; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Enzyme Activation; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Neurons; Protein Isoforms; Unfolded Protein Response
PubMed: 22190742
DOI: 10.1091/mbc.E11-06-0573 -
Antibodies (Basel, Switzerland) Jun 2022Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality.... (Review)
Review
Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality. Patients typically suffer from severe itch with eczematous lesions, urticarial plaques, and/or tense blisters. BP is characterized by the presence of circulating autoantibodies against two components of the hemidesmosome, BP180 and BP230. The transmembrane BP180, also known as type XVII collagen or BPAG2, represents the primary pathogenic autoantigen in BP, whereas the intracellular BP230 autoantigen is thought to play a minor role in disease pathogenesis. Although experimental data exist suggesting that anti-BP230 antibodies are secondarily formed following initial tissue damage mediated by antibodies targeting extracellular antigenic regions of BP180, there is emerging evidence that anti-BP230 IgG autoantibodies alone directly contribute to tissue damage. It has been further claimed that a subset of patients has a milder variant of BP driven solely by anti-BP230 autoantibodies. Furthermore, the presence of anti-BP230 autoantibodies might correlate with distinct clinical features. This review summarizes the current understanding of the role of BP230 and anti-BP230 antibodies in BP pathogenesis.
PubMed: 35892704
DOI: 10.3390/antib11030044 -
Disease Models & Mechanisms May 2020Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently,...
Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, -related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single locus produces at least three major isoforms: (neuronal isoform), (muscular isoform) and (epithelial isoform). () mice, which have mutations in , were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of -related diseases, we investigated two mutant strains with different mutations: a spontaneous mutant ( mice) and a gene-trap mutant ( mice). The allele possesses a nonsense mutation in an exon shared by all isoforms. The allele is predicted to inactivate and isoforms but not There was a decrease in the levels of mRNA in the neural tissue of both and homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both and mice at postnatal stages. In contrast, mRNA expression was reduced in the skin of mice but not in mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with mRNAs. Because encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of mice but not in those of mice; thus, the distinct phenotype of the skin of mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the locus can cause different loss-of-function patterns among isoforms, which accounts for the heterogeneous neural and skin phenotypes in mice and -related diseases.
Topics: Animals; Desmosomes; Disease Models, Animal; Dystonic Disorders; Dystonin; Gene Expression Regulation; Homozygote; Mice; Mutation; Neurons; Phenotype; Protein Isoforms; RNA, Messenger; Skin
PubMed: 32482619
DOI: 10.1242/dmm.041608 -
PloS One 2023The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying...
The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong candidate genes including dystonin (Dst/Bpag1). Here, CRISPR/Cas9 was used to alter exon 23 in mouse skin specific isoform Dst-e (Ensembl GRCm38 transcript name Dst-213, transcript ID ENSMUST00000183302.5, protein size 2639AA) and validate a proposed arginine/glutamine difference at amino acid p1226 in B6 versus 129 mice as a modifier of EB. Frame shift deletions (FSD) in mouse Dst-e exon 23 (Dst-eFSD/FSD) were also identified that cause mice carrying wild-type Lamc2 to develop a phenotype similar to human EB simplex without dystonia musculorum. When combined, Dst-eFSD/FSD modifies Lamc2jeb/jeb (FSD+jeb) induced disease in unexpected ways implicating an altered balance between DST-e (BPAG1e) and a rarely reported rodless DST-eS (BPAG1eS) in epithelium as a possible mechanism. Further, FSD+jeb mice with pinnae removed are found to provide a test bed for studying internal epithelium EB disease and treatment without severe skin disease as a limiting factor while also revealing and accelerating significant nasopharynx symptoms present but not previously noted in Lamc2jeb/jeb mice.
Topics: Animals; Mice; Dystonia; Dystonic Disorders; Dystonin; Epidermolysis Bullosa; Epidermolysis Bullosa Simplex; Epidermolysis Bullosa, Junctional; Skin
PubMed: 37883475
DOI: 10.1371/journal.pone.0293218 -
Frontiers in Immunology 2019Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting cellular adhesion molecules. While IgE autoantibodies are... (Review)
Review
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting cellular adhesion molecules. While IgE autoantibodies are occasionally reported in other autoimmune blistering diseases, BP is unique in that most BP patients develop an IgE autoantibody response. It is not known why BP patients develop self-reactive IgE and the precise role of IgE in BP pathogenesis is not fully understood. However, clinical evidence suggests an association between elevated IgE antibodies and eosinophilia in BP patients. Since eosinophils are multipotent effector cells, capable cytotoxicity and immune modulation, the putative interaction between IgE and eosinophils is a primary focus in current studies aimed at understanding the key components of disease pathogenesis. In this review, we provide an overview of BP pathogenesis, highlighting clinical and experimental evidence supporting central roles for IgE and eosinophils as independent mediators of disease and via their interaction. Additionally, therapeutics targeting IgE, the Th2 axis, or eosinophils are also discussed.
Topics: Antibodies, Monoclonal, Humanized; Autoantibodies; Cytokines; Dystonin; Eosinophilia; Eosinophils; Humans; Immunoglobulin E; Immunoglobulin G; Immunoglobulins, Intravenous; Pemphigoid, Bullous; Receptors, IgE
PubMed: 31636640
DOI: 10.3389/fimmu.2019.02331 -
Neurology. Genetics Oct 2020To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.
OBJECTIVE
To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.
METHODS
Whole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing.
RESULTS
We identified compound heterozygous mutations in dystonin (), which is alternatively spliced to create many plakin family linker proteins (named the bullous pemphigoid antigen 1 [BPAG1] proteins) that function to bridge cytoskeletal filament networks. One mutation (c.250C>T) is predicted to cause a nonsense mutation (p.R84X) that only affects isoform 2 variants, which have an N-terminal transmembrane domain; the other (c.8283+1G>A) mutates a consensus splice donor site and results in a 22 amino acid in-frame deletion in the spectrin repeat domain of all BPAG1a and BPAG1b isoforms.
CONCLUSIONS
These findings introduce a novel human phenotype, axonal Charcot-Marie-Tooth, of recessive mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.
PubMed: 32802955
DOI: 10.1212/NXG.0000000000000496 -
Actas Dermo-sifiliograficas Oct 2016
Review
Topics: Adult; Autoantibodies; Autoantigens; Azathioprine; Biopsy; Diagnosis, Differential; Drug Therapy, Combination; Dystonin; Erythema Multiforme; Female; Humans; Immunosuppressive Agents; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prednisone; Collagen Type XVII
PubMed: 27048923
DOI: 10.1016/j.ad.2016.02.008 -
Frontiers in Immunology 2019There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are... (Review)
Review
There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature.
Topics: Autoantibodies; Autoantigens; Autoimmunity; Blood Coagulation; Comorbidity; Complement Activation; Dystonin; Humans; Leukocytes; Neurodegenerative Diseases; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pinocytosis; Thrombosis; Vitamin D Deficiency; Collagen Type XVII
PubMed: 31312206
DOI: 10.3389/fimmu.2019.01506 -
Human Molecular Genetics May 2014A newly identified lethal form of hereditary sensory and autonomic neuropathy (HSAN), designated HSAN-VI, is caused by a homozygous mutation in the bullous pemphigoid...
Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI.
A newly identified lethal form of hereditary sensory and autonomic neuropathy (HSAN), designated HSAN-VI, is caused by a homozygous mutation in the bullous pemphigoid antigen 1 (BPAG1)/dystonin gene (DST). The HSAN-VI mutation impacts all major neuronal BPAG1/dystonin protein isoforms: dystonin-a1, -a2 and -a3. Homozygous mutations in the murine Dst gene cause a severe sensory neuropathy termed dystonia musculorum (dt). Phenotypically, dt mice are similar to HSAN-VI patients, manifesting progressive limb contractures, dystonia, dysautonomia and early postnatal death. To obtain a better molecular understanding of disease pathogenesis in HSAN-VI patients and the dt disorder, we generated transgenic mice expressing a myc-tagged dystonin-a2 protein under the regulation of the neuronal prion protein promoter on the dt(Tg4/Tg4) background, which is devoid of endogenous dystonin-a1 and -a2, but does express dystonin-a3. Restoring dystonin-a2 expression in the nervous system, particularly within sensory neurons, prevented the disorganization of organelle membranes and microtubule networks, attenuated the degeneration of sensory neuron subtypes and ameliorated the phenotype and increased life span in these mice. Despite these improvements, complete rescue was not observed likely because of inadequate expression of the transgene. Taken together, this study provides needed insight into the molecular basis of the dt disorder and other peripheral neuropathies including HSAN-VI.
Topics: Animals; Carrier Proteins; Cells, Cultured; Cytoskeletal Proteins; Disease Models, Animal; Dystonia Musculorum Deformans; Dystonin; Ganglia, Spinal; Hereditary Sensory and Autonomic Neuropathies; Humans; Intracellular Membranes; Mice, Inbred C57BL; Mice, Transgenic; Microtubules; Muscle Spindles; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Neuromuscular Junction; Phenotype; Proprioception; Sensory Receptor Cells; Transgenes
PubMed: 24381311
DOI: 10.1093/hmg/ddt663 -
Genetics Sep 2016Dystonia 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...
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.
Topics: Alleles; Animals; Axons; Central Nervous System; Dystonic Disorders; Dystonin; Female; Gene Deletion; Male; Mice; Mice, Inbred C57BL; Mutation; Nerve Tissue Proteins; Neurons
PubMed: 27401753
DOI: 10.1534/genetics.116.186932