Amino acid substitution in the cysteine rich region of the integrin β4 subunit causes late onset mild junctional epidermolysis bullosa without extracutaneous involvement.

Integrin α6β4, encoded by ITGA6 and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4 or ITGA6 biallelic pathogenic variants cause junctional epidermolysis bullosa with pyloric atresia (JEB-PA), which is associated with high lethality. Patients that survive usually develop JEB of intermediate severity and uro-renal manifestations. Here, we report a very rare subtype of late-onset non-syndromic JEB associated with a recurrent amino acid substitution in the highly conserved cysteine-rich tandem repeats of the integrin β4 subunit. Literature review shows that among the patients diagnosed with ITGB4 mutations, only two had no extracutaneous manifestations, and only two patients with JEB-PA carried missense mutations located in cysteine-rich tandem repeats. We analyzed the consequences of the novel variant ITGB4, c.1642G>A, p.Gly548Arg on the clinical phenotype, the predicted protein structure, cellular phenotype and gene expression pattern to demonstrate its pathogenicity. The results indicated that the p.Gly548Arg amino acid substitution affected the protein structure of integrin β4 subunits and disrupted the stability of hemidesmosomes, and in turn impaired the adhesion of keratinocytes. RNA-seq results indicated similar changes in "ECM structure organization" and "differentiation" in keratinocytes completely devoid of integrin β4 and with the amino acid substitution p.Gly548Arg, which further supports the dysregulation of the function of the integrin β4 subunit caused by p.Gly548Arg. Our results provided evidence for a late onset mild JEB subtype without extracutaneous manifestations and extend the ITGB4 related genotype-phenotype correlations.