TT virus (TTV) is a newly identified human DNA virus of the family Circoviridae. Its genome consists of six putative open reading frames (ORFs). TTV was isolated originally from a patient with cryptogenic hepatitis and the association of TTV with hepatitis has been studied extensively, while its significance in other diseases is unknown. To examine the pathogenicity of TTV, mice transgenic for the ORF genes in various combinations were produced. A total of 11 independent founder mice was produced: two mice, which were found to carry the ORF1 gene, showed pathological changes in the kidney; other tissues were not affected. In these mice, the transgene was expressed most strongly in the kidney and the transcript was shown to be spliced to encode a protamine-like, highly basic protein. Mice from a line with high transgene expression developed renal failure with severe renal epithelial cell abnormalities resembling those seen in humans with nephrotic syndrome. The transgenic mice with severe ascites died before reaching the age of 5 weeks. Another founder mouse with low expression levels also showed similar, but milder, renal epithelial cell changes, indicating that these effects were not caused by the insertion of the transgene, but, rather, were caused by the ORF1 gene product. These observations suggest that TTV affects renal epithelial cells as part of the naturally occurring infection.