Folliculin forms a complex with folliculin-interacting proteins 1 and 2 (FNIP1 and FNIP2), and 5'-AMP-activated protein kinase (AMPK), an important energy sensor in cells that negatively regulates mammalian target of rapamycin (mTOR). Folliculin plays a role in the regulation of key molecules in TGF-beta signaling. Folliculin is a tumor suppressor (Hong SB et al. 2010).
Defects in FLCN are the cause of Birt-Hogg-Dube syndrome (BHD). BHD is a rare autosomal dominant genodermatosis characterized by hair follicle hamartomas (fibrofolliculomas), kidney tumors, and spontaneous pneumothorax. Fibrofolliculomas are part of the triad of BHD skin lesions that also includes trichodiscomas and acrochordons. Onset of this dermatologic condition is invariably in adulthood. BHD is associated with a variety of histologic types of renal tumors, including chromophobe renal cell carcinoma (RCC), benign renal oncocytoma, clear-cell RCC and papillary type I RCC. Multiple lipomas, angiolipomas, and parathyroid adenomas are also seen in patients affected with this disease. The majority of mutations are predicted to prematurely terminate the protein.
BHD syndrome is characterized by a spectrum of mutations (at least 23 different germline mutations, of various types), and clinical heterogeneity both among and within families (Toro JR et al. 2008). All germline mutations are predicted to truncate the mutant protein. Mutations are located along the entire length of the coding region, with no genotype-phenotype correlations noted between type of mutation, location within the gene and phenotypic disease manifestations. More than 50% of mutations have been observed in a “hotspot” in exon 11
FLCN/BHD somatic mutations have been found at only a very low frequency (0-10%) in sporadic renal tumors and therefore, may not represent a major mechanism for the development of sporadic renal carcinoma. Loss of 17p DNA including p53 (36%) or partial methylation (28%) of the FLCN/BHD promoter were reported in sporadic renal carcinomas with various histologies.
Mutations have been identified in the mutational hot spot in exon 11 of the FLCN/BHD gene in other tumor types exhibiting microsatellite instability, including colorectal carcinoma (20%), endometrial carcinoma (12%) and gastric carcinoma (16%).
References (open access) :
Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS. Mol Cancer. 2010 Jun 23;9:160.
BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. J Med Genet. 2008 Jun;45(6):321-31.