The study of some germline missense mutations in the folliculin gene, such as H255Y and K508R, observed in BHD patients with renal carcinomas has directly supported their pathogenic role: the FLCN H255Y mutant protein displayed a loss of its tumor suppressive function inducing kidney cell proliferation and the clinical manifestations of BHD, the FLCN K508R mutant protein exerted a dominant negative effect on the function of WT FLCN in the regulation of kidney cell proliferation [98]. This evidence concerns the gene FLCN and Birt-Hogg-Dube syndrome.