An ITGB4 variant modifies the severity of ITGA3-associated interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB).

Biallelic ITGA3 variants cause a rare subtype of junctional epidermolysis bullosa named interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa is characterized by extensive clinical heterogeneity, suggesting the existence of modifier genes. We studied a family with 2 siblings affected by interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa due to a homozygous ITGA3 variant. The disease severity was strikingly different in the 2 siblings. Whole-exome sequencing revealed the presence of 2 different heterozygous variants in ITGB4 in each of the 2 patients: p.Arg977Cys in the more severely affected individual and p.Asp285Asn in the milder case. Accordingly, the ITGB4 p.Arg977Cys variant caused a significantly greater reduction in ITGB4 membrane localization than the p.Asp285Asn variant. In addition, the ITGB4 p.Arg977Cys variant resulted in significantly diminished activation of the focal adhesion kinase/protein kinase B/mTOR/S6 pathway compared with the p.Asp285Asn variant. Finally, using coimmunoprecipitation assays as well as confirmatory proximity ligation assays, we identified a hitherto unrecognized direct interaction between ITGA3 and ITGB4, which was more significantly compromised by the ITGB4 p.Arg977Cys variant than by the p.Asp285Asn variant. Our findings indicate that monoallelic ITGB4 genetic variants may modulate the severity of ITGA3-associated interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa.