Integrins are proteins that connect the extracellular matrix to the cytoskeleton, mediating the attachment of cells to the surrounding tissue. The integrin α3β1, encoded by the gene ITGA3, is expressed in the lungs and the kidneys and must be glycosylated to function properly. In this issue of the JCI, Nicolaou et al. identified a gain-of-glycosylation mutation in ITGA3 in a patient with lung disease and kidney failure. In the frames above, they compared the kidney tissue of patients with wild-type (top) and mutant (bottom) ITGA3 using indirect immunofluorescence analysis. They found that the ITGA3 mutation caused excessive glycosylation and protein degradation, which prevented the affected cells from sticking to the surrounding tissue and causing abnormalities in kidney and lung morphogenesis.
Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 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 α3 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 α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 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 α3β1, causing a fatal multiorgan disorder.
Nayia Nicolaou, Coert Margadant, Sietske H. Kevelam, Marc R. Lilien, Michiel J.S. Oosterveld, Maaike Kreft, Albertien M. van Eerde, Rolph Pfundt, Paulien A. Terhal, Bert van der Zwaag, Peter G.J. Nikkels, Norman Sachs, Roel Goldschmeding, Nine V.A.M. Knoers, Kirsten Y. Renkema, Arnoud Sonnenberg