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 (beta 4GalT-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 beta 4GalT-I-deficient mice. Hematuria was detected in some of the beta 4GaIT-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 beta 4GalT-I-deficient mice. These results demonstrate that the beta 4GalT-I-deficient mice developed IgAN-like disease. Furthermore, high serum IgA levels with increased polymeric forms were detected. In humans, serum IgA derived from patients with IgAN has aberrant beta 3-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, beta 4-galactosylation on the N-glycans of the serum IgA of the beta 4GalT-I-deficient mice was completely absent. This is the first report demonstrating that genetic remodeling of protein glycosylation causes IgAN. We suggest that aberrant beta 4-galactosylation of serum IgA participates in the development of IgAN, including deposition of IgA, polymerization of TgA, and glomerular injury after IgA deposition. Copyright (c) 2007 S. Karger AG, Basel.