Genetics This diagram shows how autosomal dominant disorders like BHD are passed on. The unaffected parent produces all normal gametes (sperm and egg) and the affected parent produces half mutant gametes and half normal gametes. Because only one copy of the mutation is needed to have an autosomal dominant disease, each offspring has a 50% chance of having the mutation. An association with the folliculin (FLCN) gene was first reported in 2002. This 14-exon gene is located on the short arm of chromosome 17 (17p11.2) and has a cytosine-rich region in exon 11 particularly susceptible to mutation. The most common mutation in this region is the insertion or deletion of a cytosine residue, found in 53% of BHD-affected families. No significant difference has been found in the symptoms experienced by families with an insertion at that location compared to those who have a deletion, but mutations in FLCN associated with BHD<unk>  are heterogeneous, and are often nonsense mutations or frameshift mutations that cause early truncation of the protein product at the carboxy terminus. Very rarely, missense mutations are observed. The mutations in the FLCN gene that cause<unk> -Hogg-Dubé<unk>  are germline mutations, which means that they occur in every cell of the body and can be passed down to future generations. These mutations are often passed from one generation to the next in an autosomal dominant fashion, but can occur as a new mutation in an individual with no prior family history (a de novo mutation). The children of an affected parent each has a 50% chance of having the disease. BHD has very high penetrance. A correlation between different FLCN genotypes and phenotypes has not been discovered. Function FLCN creates a protein, folliculin, that has two isoforms. It appears to act as a tumor suppressor, and is expressed strongly in the skin, distal nephrons, and type I pneumocytes. It has also been found in the parotid gland, brain, breast, pancreas, prostate, and ovaries. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the FLCN gene may interfere with the ability of folliculin to restrain cell growth and division, leading to the formation of noncancerous and cancerous tumors. Recent studies suggest that folliculin accomplishes this function through its involvement with cellular metabolism, possibly through modulation of the mTOR (mammalian target of rapamycin) pathway and/or oxidative phosphorylation in mitochondria. Folliculin interacts with FNIP1 and FNIP2 (FLCN-interacting protein) to form a complex with AMP-activated protein kinase. Folliculin's participation in the mTOR pathway may explain the similarity in phenotype between BHD<unk> , Cowden<unk> , tuberous sclerosis, and Peutz–Jeghers<unk> . Most of the cancer-causing mutations cause the protein to be truncated at the carboxy terminus. The C-terminal end of folliculin has shown to be 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. Folliculin is encoded by the FLCN gene, located on the p arm of human chromosome 17. 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.
Birt–Hogg–Dubé syndrome
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Cruveilhier–Baumgarten disease
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Beare–Stevenson cutis gyrata syndrome
Sézary disease
Ardalan–Shoja–Kiuru syndrome