TY - JOUR
T1 - Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome
AU - Nicolaou, Nayia
AU - Margadant, Coert
AU - Kevelam, Sietske H.
AU - Lilien, Marc R.
AU - Oosterveld, Michiel J. S.
AU - Kreft, Maaike
AU - van Eerde, Albertien M.
AU - Pfundt, Rolph
AU - Terhal, Paulien A.
AU - van der Zwaag, Bert
AU - Nikkels, Peter G. J.
AU - Sachs, Norman
AU - Goldschmeding, Roel
AU - Knoers, Nine V. A. M.
AU - Renkema, Kirsten Y.
AU - Sonnenberg, Arnoud
PY - 2012
Y1 - 2012
N2 - 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
AB - 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
U2 - https://doi.org/10.1172/JCI64100
DO - https://doi.org/10.1172/JCI64100
M3 - Article
C2 - 23114595
SN - 0021-9738
VL - 122
SP - 4375
EP - 4387
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 12
ER -