Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype.
Human skin graft mouse models are widely used to investigate and develop therapeutic strategies for the severe generalized form of recessive dystrophic epidermolysis bullosa (RDEB), which is caused by biallelic null mutations in COL7A1 and the complete absence of type VII collagen (C7). Most therapeutic approaches are focused on reintroducing C7. Therefore, C7 and anchoring fibrils are widely used as readouts in therapeutic research with skin graft models. In this study, we investigated the expression pattern of human and murine C7 in a grafting model, in which human skin is reconstituted out of in vitro cultured keratinocytes and fibroblasts. The model revealed that murine C7 was deposited in both human healthy control and RDEB skin grafts. Moreover, we found that murine C7 is able to form anchoring fibrils in human grafts. Therefore, we advocate the use of human-specific antibodies when assessing the reintroduction of C7 using RDEB skin graft mouse models.
Atopic dermatitis (AD) is a common allergic and immunological skin disease. Mutations in the gene encoding filaggrin (FLG) were shown to be predisposing factors for AD in various populations. However, the rate of FLG mutations in AD is low in some populations. Studies have shown that patients without FLG mutations also have reduced filaggrin expression suggesting that other factors controlling filaggrin expression, including promoter polymorphism, might be important. The involvement of FLG promoter polymorphism in AD has not been determined. In this study, we performed genetic analysis of FLG promoter region in AD (n¼68) and related disease, ichthyosis vulgaris (IV) (n¼24), to determine whether FLG promoter polymorphisms associate with AD and IV. PCR and direct DNA sequencing of a 1.2kb DNA fragment representing FLG promoter region revealed an A>G polymorphism at-533 relative to the transcription start site. The A/A genotype was found in 47%, 58.3% and 44% of AD, IV and normal controls, respectively. The A/G genotype was found in 25%, 33.3% and 44% of AD, IV and normal controls, respectively. The G/G genotype was found in 28%, 8.3% and 12% of AD, IV and normal controls, respectively. Statistical analyses revealed that the G/G genotype was over represented in AD and significantly associated with AD (p¼0.006) but not IV (p¼0.472) compared with normal controls. Allele frequency was not different. To determine transcriptional differences between the genotypes, we performed FLG promoter activity assay in keratinocytes and found that the G allele have reduced promoter activity (p<0.05). Together, our study suggested that FLG promoter polymorphisms are significantly associated with AD and may explain differences in FLG expression in AD.
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