Gain of glycosylation in integrin ?3 causes lung disease and nephrotic syndrome.

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

SUBMITTER: Nicolaou N 

PROVIDER: S-EPMC3533548 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature