A deep intronic splicing mutation in LAMB3 causes systemic inflammation in severe junctional epidermolysis bullosa amenable to targeted therapy

Abstract Background Junctional epidermolysis bullosa (JEB) is a rare hereditary skin disease with high mortality in its severe JEB subtype. Most severe JEB cases result from nonsense mutations in LAMB3 exons, while the role of non-coding variants remains elusive. Though systemic inflammation has been described in some subtypes of epidermolysis bullosa, the nature and underlying mechanisms of this inflammation in severe JEB are unknown. Results Here, we report a severe JEB patient with typical cutaneous fragility and systemic inflammatory activation. Whole-genome sequencing (WGS) identified compound heterozygous mutations of LAMB3 , including a novel deep intronic variant (c.3382 + 244G > A). Functional assays confirmed that both variants induced aberrant pre-mRNA splicing, created premature termination codons (PTCs), and markedly reduced laminin-332 β3 mRNA and protein levels, consistent with nonsense-mediated mRNA decay. With more comprehensive immunological profiling, we discovered a systemic inflammatory state dominated by Th1 and Th17 cellular responses, with hyperactivation of TNF-α/NF-κB and JAK-STAT signaling pathways. Based on these molecular insights, targeted therapy with the TNF-α inhibitor adalimumab was initiated and led to substantial clinical improvement. In contrast, treatment with the JAK1/2 inhibitor baricitinib conferred only transient benefit, followed by relapse associated with persistent NF-κB activation. Conclusion Our findings identify a mechanistic link between a deep intronic LAMB3 mutation and a severe JEB phenotype with systemic inflammation, implicate the TNF-α/NF-κB axis as a major inflammatory pathway and emphasize the potential of targeted anti-cytokine therapy. Our study broadens JEB genetics, highlights WGS for identifying potentially pathogenic non-coding variants, and suggests a promising precision medicine approach to inflammatory complications of severe JEB.