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: Ebru G Yalcin, Yinghong He, Diclehan Orhan, Chiara Pazzagli, Nagehan Emiralioglu, Cristina Has
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 13 Pg. 3679-88 (Jul 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25810266 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Integrin alpha3

Topics

• Amino Acid Substitution
• Base Sequence
• Humans
• Infant, Newborn
• Integrin alpha3 (genetics, metabolism)
• Lung Diseases, Interstitial (genetics, metabolism)
• Male
• Molecular Sequence Data
• Mutation, Missense
• Nephrotic Syndrome (genetics, metabolism)
• Protein Processing, Post-Translational