Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Katharina Brandl, Wataru Tomisato, Xiaohong Li, Christina Neppl, Elaine Pirie, Werner Falk, Yu Xia, Eva Marie Y Moresco, Roberto Baccala, Argyrios N. Theofilopoulos, Bernd Schnabl, Bruce Beutler

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Abstract

Using an environmentally sensitized genetic screen we identified mutations that cause inflammatory colitis in mice. The X-linked Klein-Zschocher (KLZ) mutation created a null allele of Yipf6, a member of a gene family believed to regulate vesicular transport in yeast, but without known functions in mammals. Yipf6 is a five transmembrane-spanning protein associated with Golgi compartments. Klein-Zschocher mutants were extremely sensitive to colitis induced by dextran sodium sulfate (DSS) and developed spontaneous ileitis and colitis after 16 mo of age in specific pathogen-free housing conditions. Electron microscopy, gene expression, and immunocytochemistry analyses provided evidence that impaired intestinal homeostasis stemmed from defective formation and secretion of large secretory granules from Paneth and goblet cells. These studies support a tissue- and organ-specific function for Yipf6 in the maintenance of intestinal homeostasis and implicate the orthologous human gene as a disease susceptibility locus.

Original languageEnglish (US)
Pages (from-to)12650-12655
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number31
DOIs
StatePublished - Jul 31 2012

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Brandl, K., Tomisato, W., Li, X., Neppl, C., Pirie, E., Falk, W., Xia, Y., Moresco, E. M. Y., Baccala, R., Theofilopoulos, A. N., Schnabl, B., & Beutler, B. (2012). Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice. Proceedings of the National Academy of Sciences of the United States of America, 109(31), 12650-12655. https://doi.org/10.1073/pnas.1210366109