Study of a novel autoantigen related to autoimmune enteropathy with renal tubular dysfunction

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Autoimmune enteropathy is a rare desease characterized by circulating autoantibody against epithelial cells of the intestine. Some cases are inherited by an X-linked manner and named immunedysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). The aim of our study is to identity the target of the autoantibody and to clarify the biological functions of the antigen.For this purpose, we screened λgt11 cDNA expression library from human duodenum with the serum from an IPEX patient, and identified a cDNA encoding a novel protein consisting of 552 amino acids. The protein named autoimmune, enteropathy-related 75 kDa antigen (AIE-75) predominantly distributed to the brush border in the small intestine and proximal renal tubulus. AIE-75 gene was mapped to chromosome 11p14.3. In collaboration with C. Petit of the Pasteur Institute, we demonstrated that AIE-75 also distributed to the epithelial cells in the inner ear and that mutation of the gene caused a hereditary deafness, Usher syndrome type 1C. This suggests that AIE-75 plays a biologically significant rolls in not only the small intestine and kidney but also in the inner ear.AIE-75 contains three PDZ domains, suggesting that the protein functions as a linker protein. Using yeast two-hybrid screening, we identified a novel protein homologous to a tumor suppressor, MCC, and named MCC-2. In addition, overexpression of AIE-75 in a colon cancer cell line, SW480, which lacks AIE-75 resulted in G2/M arrest. These findings suggest that AIE-75 is involved in the regulation of cell cycle. Recently, a forkhead/winged helix transcription regulator, FOXP3, has been identified as a causative gene of IPEX. We reported two novel mutation of FOXP3 in Japanese patients with IPEX and suggested that Ile363 is necessary for the normal function of FOXP3.