Giuseppina Spartà and colleagues identify mutations in the ITGA3 gene (encoding integrin α3) as the cause of a rare congenital disorder characterized by disrupted basement membrane structures in multiple epithelial organs (N. Engl. J. Med. 366, 1508–1514, 2012). The authors examined three unrelated subjects with overlapping clinical features that included nephrotic syndrome, interstitial lung disease and blistering skin lesions. Histological and immunofluorescence analyses of affected skin samples showed disruptions in the basement membrane and a lack of integrin α3 protein. Consistent with these findings, candidate gene sequencing identified homozygous ITGA3 mutations in all three affected individuals. The clinical features of this syndrome overlap with the phenotype of Itga3 knockout mice, which die shortly after birth with multiple defects in kidney, lung and skin tissues. Mutations in the gene encoding integrin β4 (ITGB4), which forms functional heterodimers with integrin α3, cause a similar skin blistering phenotype (Nat. Genet. 10, 229–234, 1995). These findings underscore the importance of integrins in maintaining epithelial integrity and show how histological findings can aid clinical diagnoses and help elucidate the genetic causes of rare congenital disorders. KV