title: Development of immunoglobulin A nephropathy- like disease in beta-1,4-galactosyltransferase-I-deficient mice.
abstract: Beta4 galactosylation of glycoproteins plays important roles in protein conformation, stability, transport, and clearance from the circulation. Recent studies have revealed that aberrant glycosylation causes various human diseases. Here we report that mice lacking beta-1,4-galactosyltransferase (beta4GalT)-I, which transfers galactose to the terminal N-acetylglucosamine of N- and O-linked glycans in a beta-1,4 linkage, spontaneously developed human immunoglobulin A nephropathy (IgAN)-like glomerular lesions with IgA deposition and expanded mesangial matrix. beta4GalT-I-deficient mice also showed high serum IgA levels with increased polymeric forms as in human IgAN. IgAN is the most common form of glomerulonephritis, and a significant proportion of patients progress to renal failure. However, pathological molecular mechanisms of IgAN are poorly understood. In humans, abnormal character of serum IgA, especially serum IgA1 with aberrant galactosylation and sialylation of O-glycans in its hinge region is thought to contribute to the pathogenesis of IgAN. Mouse IgA has N-glycans but not O-glycans, and beta4-galactosylation and sialylation of the N-glycans on the serum IgA from beta4GalT-I-deficient mice was completely absent. This is the first report demonstrating that genetic remodeling of protein glycosylation causes IgAN. We propose that carbohydrates of serum IgA are involved in the development of IgAN, whether the carbohydrates are O-glycans or N-glycans.
authors.affiliation: Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
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; D005700:Galactosyltransferases / Q000172:deficiency* / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046188:Protein Modification, Translational / Q000235:genetics; D051437:Renal Insufficiency / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D007070:Immunoglobulin A; D005700:Galactosyltransferases; C119701:beta-1,4-galactosyltransferase I