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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 -
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 -
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