title: Development of IgA nephropathy-like disease with high serum IgA levels and increased proportion of polymeric IgA in Beta-1,4-galactosyltransferase-deficient mice.
abstract: The glycosylation of glycoproteins is important for their biological activity, conformation and stability. Recent studies indicate that aberrant glycosylation causes various human disorders. Here we report that mice lacking beta-1,4-galactosyltransferase-I (beta4GalT-I), which transfers galactose from UDP-Gal to terminal GlcNAc of N- and O-glycans in a beta-1,4- linkage, developed IgA nephropathy (IgAN)-like disease. Urinary albumin levels were significantly increased in the beta4GalT-I-deficient mice. Hematuria was detected in some of the beta4GalT-I-deficient mice, suggesting impaired renal function. Furthermore, histological and immunohistochemical examination showed expanded mesangial matrix, IgA deposition with mesangial pattern and electron-dense deposits in the paramesangial regions in the beta4GalT-Ideficient mice. These results demonstrate that the beta4GalT-I-deficient mice developed IgANlike disease. Furthermore, high serum IgA levels with increased polymeric forms were detected. In humans, serum IgA derived from patients with IgAN has aberrant beta3-galactosylation and sialylation on its O-linked glycans of the hinge region. Mouse IgA does not have O-glycans of the hinge region and has several N-glycans. As expected, beta4-galactosylation on the N-glycans of the serum IgA of the beta4GalT-I-deficient mice was completely absent. This is the first report demonstrating that genetic remodeling of protein glycosylation causes IgAN. We suggest that aberrant beta4-galactosylation of serum IgA participates in the Nishie/Miyaishi/Azuma/Kameyama/Naruse/Hashimoto/Yokoyama/Narimatsu/Wada/Asano 126 development of IgAN, including deposition of IgA, polymerization of IgA, and glomerular injury after IgA deposition.
authors.affiliation: Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan. asano@kiea.m.kanazawa-u.ac.jp
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nishie
authors.forename: Osamu
authors.initials: O
authors.lastname: Miyaishi
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kameyama
authors.forename: Chie
authors.initials: C
authors.lastname: Naruse
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narimatsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood*; D051379:Mice; D008817:Mice, Mutant Strains; D009237:N-Acetyllactosamine Synthase / Q000235:genetics*
chemical_list: D007070:Immunoglobulin A; D009237:N-Acetyllactosamine Synthase