title: 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.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nayia
authors.initials: N
authors.lastname: Nicolaou
authors.forename: Coert
authors.initials: C
authors.lastname: Margadant
authors.forename: Sietske H
authors.initials: SH
authors.lastname: Kevelam
authors.forename: Marc R
authors.initials: MR
authors.lastname: Lilien
authors.forename: Michiel J S
authors.initials: MJ
authors.lastname: Oosterveld
authors.forename: Maaike
authors.initials: M
authors.lastname: Kreft
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Peter G J
authors.initials: PG
authors.lastname: Nikkels
authors.forename: Norman
authors.initials: N
authors.lastname: Sachs
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D007223:Infant; D039422:Integrin alpha3 / Q000235:genetics* / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009404:Nephrotic Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D059748:Proteolysis; D017422:Sequence Analysis, DNA; D060185:Tetraspanin 24 / Q000378:metabolism
chemical_list: C554715:CD151 protein, human; D039422:Integrin alpha3; D019012:Integrin beta1; D060185:Tetraspanin 24; D046988:Proteasome Endopeptidase Complex