Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome
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
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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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 9

Model summarizing the biosynthetic route of CD151 and wild-type and mutant integrin α3β1.

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Model summarizing the biosynthetic route of CD151 and wild-type and muta...
Newly synthesized α3 and β1 precursors, as well as CD151, undergo N-glycosylation and folding in the ER, facilitated by the chaperone calnexin. Thereafter, CD151 can associate with other tetraspanins or associate with the α3 subunit prior to α/β heterodimerization. Properly folded and assembled complexes then traffic to the Golgi apparatus as integrin α3β1 heterodimers, α3β1 heterodimers in association with CD151, or CD151 in complex with other tetraspanins. (A) In the Golgi, the high-mannose oligosaccharides are processed to complex type sugars, and the α3 subunit is cleaved into a heavy and a light chain to generate the mature α3β1 heterodimer. (B) Gain-of-glycosylation mutations in an integrin subunit can cause a failure to reach the final conformation and thereby prevent α/β heterodimerization. The affected subunits are then cleared by the ubiquitin/proteasome system, whereas their partners accumulate in the ER.