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.