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The Birt–Hogg–Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene,  BHD , has been identified by positional cloning and thought to be a novel tumor suppressor gene.  BHD  mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the  Ksp-Cre  gene knockout system, we have developed a kidney-specific  BHD  knockout mouse model.  BHD flox/flox /Ksp-Cre  mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected  BHD flox/flox /Ksp-Cre  mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of  BHD  flox/+ /Ksp-Cre  and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of  BHD  and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the  BHD  product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome–related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.

Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia