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Journal of Dermatological Science May 2024Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the...
BACKGROUND
Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce.
OBJECTIVE
To assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics.
METHODS
BP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments.
RESULTS
We demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024-2349 and C3; amino acids 2326-2649), provided the best serological assay for anti-BP230 IgE detection.
CONCLUSION
As a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.
Topics: Humans; Pemphigoid, Bullous; Immunoglobulin E; Autoantibodies; Male; Female; Aged; Autoantigens; Dystonin; Aged, 80 and over; Non-Fibrillar Collagens; Middle Aged; Enzyme-Linked Immunosorbent Assay; Severity of Illness Index; Immunoglobulin G; Collagen Type XVII; Adult; Blotting, Western
PubMed: 38582700
DOI: 10.1016/j.jdermsci.2024.03.009 -
Journal of Neurogenetics 2023is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive () spontaneous mouse mutation causes degeneration of... (Review)
Review
is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive () spontaneous mouse mutation causes degeneration of spinocerebellar tracts as well as peripheral sensory nerves, dorsal root ganglia, and cranial nerve ganglia. In addition to mutants, axonopathy and neurofilament accumulation in perikarya are features of two other murine lines with spontaneous mutations, targeted knockout mice, Tg4 transgenic mice carrying two deleted exons, mice with trapped actin-binding domain-containing isoforms, and conditional Schwann cell-specific knockout mice. As a result of nerve damage, mutants display dystonia and ataxia, as seen in several genetically modified models and their motor coordination deficits have been quantified along with the spontaneous nonsense mutant, the conditional Schwann cell-specific knockout, the conditional mutant, and the Dst-b isoform specific mutant. Recent findings in humans have associated mutations of the Dst-b isoform with hereditary sensory and autonomic neuropathies type 6 (HSAN-VI). These data should further encourage the development of genetic techniques to treat or prevent ataxic and dystonic symptoms.
Topics: Animals; Humans; Mice; Dystonia; Mice, Knockout; Mice, Transgenic; Neurobiology; Neurons; Protein Isoforms
PubMed: 38465459
DOI: 10.1080/01677063.2024.2319880 -
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 -
Cureus Aug 2023We report a case of a 3-year-old Saudi female patient as the first case reported in Saudi Arabia who is homozygous for dystonin c.3370C>T, p.(Gln1124*). At the age of 3...
We report a case of a 3-year-old Saudi female patient as the first case reported in Saudi Arabia who is homozygous for dystonin c.3370C>T, p.(Gln1124*). At the age of 3 months, the girl started to develop numerous vesicles and bullae involving the dorsum of the feet that were not on a pressure site, with remission and aggravation, but she had no mucosal lesions or nail affection. The patient was diagnosed with epidermolysis bullosa simplex.
PubMed: 37692655
DOI: 10.7759/cureus.43206 -
Anatomical Science International Jan 2024Dystonin (DST), also known as bullous pemphigoid antigen 1 (BPAG1), encodes cytoskeletal linker proteins belonging to the plakin family. The DST gene produces several... (Review)
Review
Dystonin (DST), also known as bullous pemphigoid antigen 1 (BPAG1), encodes cytoskeletal linker proteins belonging to the plakin family. The DST gene produces several isoforms, including DST-a, DST-b, and DST-e, which are expressed in neural, muscle, and cutaneous tissues, respectively. Pathogenic DST mutations cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) and epidermolysis bullosa simplex (EBS); therefore, it is important to elucidate the roles of DST isoforms in multiple organs. Recently, we have used several Dst mutant mouse strains, in which the expression of Dst isoforms is disrupted in distinct patterns, to gain new insight into how DST functions in multiple tissues. This review provides an overview of the roles played by tissue-specific DST isoforms in neural, muscle, and cutaneous tissues.
Topics: Mice; Animals; Dystonin; Cytoskeletal Proteins; Nerve Tissue Proteins; Protein Isoforms; Muscles
PubMed: 37603210
DOI: 10.1007/s12565-023-00739-1 -
PloS One 2023Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur...
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
Topics: Animals; Mice; Epidermolysis Bullosa, Junctional; Skin; Blister; Epidermis; Quantitative Trait Loci
PubMed: 37437067
DOI: 10.1371/journal.pone.0288263 -
Clinical Genetics Nov 2023Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements....
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through whole-exome sequencing combined with arrayCGH from DNA of a fetus presenting with early onset AMC, we identified biallelic loss of function variants in Dystonin (DST): a stop gain variant (NM_001144769.5:c.12208G > T:p.(Glu4070Ter)) on the neuronal isoform and a 175 kb microdeletion including exons 25-96 of this isoform on the other allele [NC_000006.11:g.(56212278_56323554)_(56499398_56507586)del]. Transmission electron microscopy of the sciatic nerve revealed abnormal morphology of the peripheral nerve with severe hypomyelination associated with dramatic reduction of fiber density which highlights the critical role of DST in peripheral nerve axonogenesis during development in human. Variants in the neuronal isoforms of DST cause hereditary sensory and autonomic neuropathy which has been reported in several unrelated families with highly variable age of onset from fetal to adult onset. Our data enlarge the disease mechanisms of neurogenic AMC.
Topics: Adult; Humans; Pregnancy; Female; Arthrogryposis; Dystonin; Hereditary Sensory and Autonomic Neuropathies; Protein Isoforms
PubMed: 37431644
DOI: 10.1111/cge.14397 -
Animals : An Open Access Journal From... Sep 2022Fecal proteomics allows for the identification of proteins and peptides present in stools and is useful in finding possible new biomarkers for diagnosing and/or...
Fecal proteomics allows for the identification of proteins and peptides present in stools and is useful in finding possible new biomarkers for diagnosing and/or monitoring gastrointestinal (GI) disorders. In the present study, we investigated the fecal proteome in healthy and diseased cheetahs (). Captive individuals of this species frequently show gastrointestinal disorders characterized by recurrent episodes of diarrhea, rare episodes of vomiting and weight loss, associated with spp. infection. Fecal proteomic evaluation has been performed by two-dimensional electrophoresis followed by liquid chromatography-tandem mass spectrometry. In healthy cheetahs, the results showed the presence of the following proteins: collagen alpha-1 (II) chain, transthyretin, IgG Fc-binding protein, titin, dystonin, isopentenyl-diphosphate Delta-isomerase 1, sodium/potassium-transporting ATPase subunit alpha-1 and protein disulfide-isomerase A6. The presence of albumin isoforms was found only in diseased cheetahs. The present paper reports the study of the fecal proteome in the cheetah, evidences some differences between healthy and diseased patients and confirms, once again, the potential of fecal proteomics for the study of the GI environment, with promising developments regarding the identification of new diagnostic/monitoring markers.
PubMed: 36139251
DOI: 10.3390/ani12182392 -
ELife Aug 2022Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause...
Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in -related diseases has been unclear. Because contains all of the -encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a -specific mutant mouse model harboring a nonsense mutation. mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.
Topics: Animals; Cardiomyopathies; Dystonin; Hereditary Sensory and Autonomic Neuropathies; Mice; Muscular Diseases; Mutation; Protein Aggregates; Protein Isoforms
PubMed: 35942699
DOI: 10.7554/eLife.78419