Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome

Integrins are transmembrane alphabeta glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin alpha3beta1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, alpha3beta1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin alpha3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the alpha3 precursor prevented its heterodimerization with beta1, whereas CD151 association with the alpha3 subunit occurred normally. Consequently, the beta1 precursor accumulated in the ER, and the mutant alpha3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional alpha3beta1, causing a fatal multiorgan disorder