Photo Credit: Miriam Doerr

The following is a summary of “Amino Acid Substitution in the Cysteine-Rich Region of the Integrin β4 Subunit Causes Late-Onset Mild Junctional Epidermolysis Bullosa without Extracutaneous Involvement,” published in the November 2023 issue of Dermatology by  Wang, et al.

Integrin α6β4, made by ITGA6 and ITGB4, is a part of hemidesmosomes that crosses membranes and is very important for connecting keratinocytes to proteins outside cells. Some genetic variations, called ITGB4 or ITGA6, can lead to junctional epidermolysis bullosa (JEB) with pyloric atresia, a very deadly condition. Patients who make it through the disease usually develop JEB of moderate intensity and urinary tract symptoms. Researchers found a very uncommon late-onset, nonsyndromic JEB linked to a repeated amino acid change in the integrin β4 subunit’s highly conserved cysteine-rich tandem repeats. 

A literature review showed that of the patients found with ITGB4 mutations, only two had no symptoms outside of the skin. Similarly, only two patients who had JEB with pyloric atresia had missense mutations in cysteine-rich tandem repeats. They looked at how the new ITGB4 mutant c.1642G>A, p.Gly548Arg affected the clinical phenotype, the expected protein structure, the cellular phenotype, and the gene expression pattern to show that it was harmful. 

The findings showed that the p.Gly548Arg amino acid change changed the shape of integrin β4 subunits, changing the stability of hemidesmosomes and making it harder for keratinocytes to stick together. RNA-sequencing showed that keratinocytes with and without the amino acid substitution p.Gly548Arg had similar changes in the organization and differentiation of the extracellular matrix structure. It supported the idea that p.Gly548Arg changes how the integrin β4 subunit works. Their findings supported the idea of a weak, late-onset JEB subtype that doesn’t show up on the skin, and they add to the body of research on how genes and appearance are linked.

Source: sciencedirect.com/science/article/abs/pii/S0022202X23020717