the domain through which it interacts with FNIP1, and thereby possibly the mTOR pathway. FLCN is highly conserved in vertebrates—it is very similar between many vertebrate species. The 508th amino acid, normally lysine, is affected by a missense mutation in some people with BHD. The lysine at this position is found to be conserved between invertebrate and vertebrate orthologs of folliculin, indicating that it is important to the protein's function. People with BHD are born with one mutated copy of the FLCN gene in each cell. Haploinsufficiency—only having one functional copy of the FLCN gene—is enough to cause the fibrofolliculomas and pulmonary cysts, though one copy of the gene is enough to keep kidney cells in check. During a person's lifetime, random mutations might inactivate the normal copy of the gene in a subset of cells. When this occurs, the result is that these cells have no functional copies of the FLCN gene, allowing the cells grow out of control. This loss of heterozygosity is a common mechanism in cancer, and it is frequently detected in the renal cancers associated with BHD. The molecular genetic defects in renal tumors of people with BHD are different from two other similar kidney tumors, chromophobe renal cell carcinoma and renal oncocytoma. BHD-associated tumorigenesis differs between the kidney, where loss of FLCN heterozygosity is responsible for cancers, and the skin, where FLCN is strongly expressed in heterozygotes. FLCN has been found to be overexpressed in fibrofolliculoma tissue, and to have very low levels of expression in affected kidneys. Furthermore, the mTOR pathway is shown to be activated in tumor tissue from both humans and mice. Renal cystogenesis and tumorigenesis in BHD have been shown to be driven by the constitutive activation of TFEB. Diagnosis BHD can be suggested by clinical findings but is definitively diagnosed by molecular genetic testing to detect mutations in the FLCN gene. The classical clinical triad includes benign growths of the hair follicles, pulmonary cysts and spontaneous pneumothorax, and bilateral, multifocal renal tumors. Clinical triad The cutaneous manifestations of BHD were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by histology. Most individuals (89%) with BHD are found to have multiple cysts in both lungs, and 24% have had one or more episodes of pneumothorax.