Background: Altered IgA1 galactosylation is involved in the pathogenesis of IgA nephropathy (IgAN). The galactosyltransferase core-1 beta3-galactosyltransferase-1 (C1GALT1) and its chaperone cosmc are specifically required for O-galactosylation of the IgA1 hinge region. Mutations in the cosmc gene result in a secondary loss of function of C1GALT1 with subsequent undergalactosylation of glycoproteins. Mosaic mutations of cosmc have been shown to result in autoimmune disease. We hypothesized that cosmc mutations might contribute to the altered IgA1 galactosylation in IgAN patients.
Methods: We studied cosmc gene sequences in genomic DNA obtained from male patients with biopsy-proven sporadic (n = 33) and familial IgAN (n = 6 patients from different families). To account for a potential mosaicism we sequenced cosmc in 10 different peripheral blood mononuclear cell DNA clones of every patient. To specifically assess potential mosaic mutations in IgA-producing cells, cosmc mutations were also analysed in DNA isolated from CD20+ B-lymphocytes from three male IgAN patients.
Results: Despite our extensive genomic analysis, the data revealed no functionally relevant cosmc gene variants in sporadic or familial IgAN cases. A cosmc gene polymorphism, rs17261572, was identified in these IgAN patients in a similar frequency as previously reported in healthy adults. A functional consequence of this polymorphism has not yet been determined.
Conclusion: Although decreased C1GALT1 activity has been implicated in the IgAN pathogenesis and cosmc chaperone mutations can cause autoimmune disease, our data provide no evidence for a relevant role of cosmc gene mutations in European patients with sporadic or familial IgAN.