Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Integrins are transmembrane alpha beta glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin alpha 3 beta 1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, alpha 3 beta 1 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 alpha 3 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 alpha 3 precursor prevented its heterodimerization with beta 1, whereas CD151 association with the alpha 3 subunit occurred normally. Consequently, the beta 1 precursor accumulated in the ER, and the mutant alpha 3 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 alpha 3 beta 1, causing a fatal multiorgan disorder.