Molecular and genetic mechanisms in junctional epidermolysis bullosa

Abstract: JEB is a group of skin fragility disorders and contains extracutaneous manifestations such as pyloric atresia, nail dystrophy and teeth amelogeneisis imperfect. Besides, JEB presents a complex genetic landscape. The proteins, encoded by genes COL17A1, ITGBA6B4, LAMA3, LAMB3, LAMC2 and ITGA3, respectively, are integral to cell-matrix adhesion structures and responsible for JEB pathogenesis. Mutations of genes above lead to the adhesion impairment of basal keratinocytes to the BM and initiate skin fragility. Our work contains three independent parts regarding the molecular and genetic basis of JEB.
In Part I, we investigated 26 patients’ genetic basis in our undiagnosed cases suspected with EB. Seven of them were identified to have pathogenic variants on COL7A1, TGM5, COL17A1, PLEC and ITGA6, respectively, by WES. Through Sanger sequencing, we excluded the LAMB4 gene as the pathogenic gene for at least 12 patients in our cohort. The heterozygous variant LAMB4, c.350G>C, p.Arg117Thr could be associated with JEB. We also showed the reduced expression of laminin b4 chain in the BM of JEB patients’ skin and suggested the potential linkage between the gene LAMB4 and JEB.
In Part II, we reported on four patients with a late onset, mild JEB phenotype without extracutaneous manifestations. They all carried the previously unreported missense variant ITGB4, c.1642G>A, p.Gly548Arg, which lead to the amino acid substitution of a glycine to arginine in the cysteine-rich region in the extracellular domain of the integrin b4 subunit. In this study, we also performed transcriptome analysis to investigate molecular consequences and proven the pathogenicity of this novel variant.
In Part III, we explored gene expression patterns of JEB keratinocytes constitutionally lacking type XVII collagen, integrin b4 subunit or laminin b3 chain, respectively. We conducted RNA sequencing to get an unbiased gene expression analysis of JEB keratinocytes, followed with the validation in additional keratinocytes cell lines and samples from JEB patients. Our results revealed the difference in morphology, heterogeneity of the gene expression profiles and similarity of the dysregulation of pro-inflammatory genes in JEB keratinocytes carrying different causative.
Taken together, our results provide precise genetic diagnosis for JEB patients, complemented the genotype-phenotype correlations of JEB and investigated genetic and molecular basis of JEB

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2024

Classification and Topics

• Keyword: Keratinozyt ; Grundsubstanz

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2024
• Creator: Wang, Yao
• Contributor: Has, Cristina ; Wrbas, Karl-Thomas ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Further information

• DOI: 10.6094/UNIFR/260603
• URN: urn:nbn:de:bsz:25-freidok-2606034
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:31 AM CEST