Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome
Nayia Nicolaou, … , Kirsten Y. Renkema, Arnoud Sonnenberg
Nayia Nicolaou, … , Kirsten Y. Renkema, Arnoud Sonnenberg
Published November 1, 2012
Citation Information: J Clin Invest. 2012;122(12):4375-4387. https://doi.org/10.1172/JCI64100.
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Research Article Nephrology

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

Abstract

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.

Authors

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

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Figure 1

Identification of homozygosity for an ITGA3 mutation in a patient with interstitial lung disease and nephrotic syndrome.

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Identification of homozygosity for an ITGA3 mutation in a patient with i...
(A) Pedigree of the patient’s family. I:1 and I:2, the patient’s parents; II:2, the patient; II:1, the patient’s sister. (B) Results from the 250k SNP array performed on the patient’s DNA. Log2 test-over-reference ratio values (y axis) for SNP loci plotted against the position on chromosome 17 (x axis). Red dots represent the log2 ratio for each SNP locus (top panel). The effective hidden Markov model outcome, with a normal test-over-reference ratio of 0. Blue dots represent the mean log2 ratio of neighboring SNPs on the array, indicating no significant copy number gains or losses (middle panel). Idiogram of chromosome 17. Green marks represent heterozygous SNP calls at particular DNA loci. The red box indicates the homozygous 19.2-Mb region, reflected by a loss of heterozygous loci. The thickness of the blue line represents the likelihood of LOH (bottom panel). (C) Idiogram of chromosome 17. The homozygous region from 17q12 to 17q23.2 is boxed. (D) Sequence analysis of ITGA3 in the patient’s parents, the patient, and the patient’s sister. The patient is homozygous for a missense mutation (c.1045G>T), resulting in the amino acid substitution p.A349S. Both the parents and the sister are heterozygous for the mutation. (E) Schematic overview of the 26 exons of the ITGA3 gene. The location of the c.1045G>T mutation in exon 7 is indicated by an asterisk. (F) Domain organization of the integrin α3 subunit. The A349S mutation is located between 2 FG-GAP repeats in the extracellular β-propeller domain.