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 syndrome 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 Birt–Hogg–Dubé syndrome 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 syndrome, Cowden syndrome, tuberous sclerosis, and Peutz–Jeghers syndrome. 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