[8] Molecular location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1) Germline mutations in the FLCN gene cause Birt–Hogg–Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors.

The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members.

[11] Birt–Hogg–Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons).

[14][15] A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome.

[22] Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene.

[30] FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK.

Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting.

[26] N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity.

[40] The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb).

BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis.

[50][51] p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity.

Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling.

[53] These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the "stretch hypothesis" as a mechanism of pulmonary cyst pathogenesis in BHD.

[55][56] BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function.

FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types.

Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells.

[59] Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia.