title: Crucial role of posttranslational modifications of integrin α3 in interstitial lung disease and nephrotic syndrome.
abstract: Interstitial lung disease, nephrotic syndrome and junctional epidermolysis bullosa is an autosomal recessive multiorgan disorder caused by mutations in the gene for the integrin α3 subunit (ITGA3). The full spectrum of manifestations and genotype-phenotype correlations is still poorly characterized. Here, we uncovered the disease-causing role and the molecular mechanisms underlying a homozygous ITGA3 mutation leading to the single amino acid substitution, p.R463W. The patient suffered from respiratory distress and episodes of cyanosis with onset in the first week of life and had a nephrotic syndrome. Although there was no clinical evidence for cutaneous fragility, the analysis of a skin sample and of skin epithelial cells enabled the direct assessment of the authentic mutant protein. We show that the mutation altered the conformation of the extracellular β-propeller domain of the integrin α3 subunit preventing correct processing of N-linked oligosaccharides, heterodimerization with β1 integrin and maturation through cleavage into heavy and light chains in the Golgi. Confocal microscopy demonstrated that the mutant protein accumulated intracellularly, but it was not present in focal adhesions or on the cell membrane as shown by flow cytometry. These findings highlight that single amino acid changes in the integrin α3 subunit may crucially alter the structure and complex processing of this integrin, completely preventing its functionality. The present report also underscores that ITGA3 mutations may account for atypical cases solely with early onset respiratory and renal involvement.
authors: Department of Pediatric Pulmonology and.
authors: Ebru G
authors: EG
authors: Yalcin
authors: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany and.
authors: Yinghong
authors: Y
authors: He
authors: Department of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors: Diclehan
authors: D
authors: Orhan
authors: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany and Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Chiara
authors: C
authors: Pazzagli
authors: Department of Pediatric Pulmonology and.
authors: Nagehan
authors: N
authors: Emiralioglu
authors: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany and cristina.has@uniklinik-freiburg.de.
authors: Cristina
authors: C
authors: Has
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D006801:Humans; D007231:Infant, Newborn; D039422:Integrin alpha3 / Q000235:genetics / Q000378:metabolism*; D017563:Lung Diseases, Interstitial / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D039422:Integrin alpha3