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Gene Review

FLCN  -  folliculin

Homo sapiens

Synonyms: BHD, BHD skin lesion fibrofolliculoma protein, Birt-Hogg-Dube syndrome protein, FLCL, Folliculin, ...
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Disease relevance of FLCN

  • A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax [1].
  • Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors [1].
  • These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function [1].
  • Because development of a pneumothorax and/or pulmonary blebs may be the earliest or the only clinical manifestation of FLCN mutations, pulmonologists should be alert to the contribution of this gene toward this familial form of emphysema [2].
  • Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm [3].

High impact information on FLCN


Chemical compound and disease context of FLCN

  • RECENT FINDINGS: In the last 18 months, mutations in the gene encoding folliculin (FLCN) have been identified in individuals with familial spontaneous pneumothorax [5].

Biological context of FLCN


Anatomical context of FLCN


Associations of FLCN with chemical compounds

  • The majority of BHD mutations were predicted to truncate the BHD protein, folliculin [3].
  • Individuals at risk or affected by BHD should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches [11].
  • The addition reaction of benzylamine (XC6H4CH2NH2) to benzylidene-3,5-heptadione (BHD; YC6H(4-)CH=C(COEt)(2)) in acetonitrile is investigated [12].
  • RESULTS: Mutational analysis of the BHD gene of the proband and the father detected 1733insC, a cytosine insertion mutation in an eight-cytosine tract (nucleotides 1733-1740) in exon 11 [13].
  • Families with BHD did not display germline mutations in the von Hippel-Lindau gene or in the tyrosine kinase domain of the MET proto-oncogene [14].

Regulatory relationships of FLCN


Other interactions of FLCN


Analytical, diagnostic and therapeutic context of FLCN

  • Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study [3].
  • BHD promoter methylation status was examined by a methylation-specific PCR assay of all of the tumors [16].
  • The Nihon rat may therefore provide insights into a tumor-suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome [8].
  • Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules [21].
  • At 7 days intervals, 2 BHD sessions were done on the same 6 hemodialysis patients: the two BHD sessions were similar, except for the membrane used (cuprophan, first study; regenerated cellulose = Bioflux, second study, 7 days later) [22].


  1. A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Painter, J.N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomäki, K. Am. J. Hum. Genet. (2005) [Pubmed]
  2. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Graham, R.B., Nolasco, M., Peterlin, B., Garcia, C.K. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  3. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Schmidt, L.S., Nickerson, M.L., Warren, M.B., Glenn, G.M., Toro, J.R., Merino, M.J., Turner, M.L., Choyke, P.L., Sharma, N., Peterson, J., Morrison, P., Maher, E.R., Walther, M.M., Zbar, B., Linehan, W.M. Am. J. Hum. Genet. (2005) [Pubmed]
  4. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Baba, M., Hong, S.B., Sharma, N., Warren, M.B., Nickerson, M.L., Iwamatsu, A., Esposito, D., Gillette, W.K., Hopkins, R.F., Hartley, J.L., Furihata, M., Oishi, S., Zhen, W., Burke, T.R., Linehan, W.M., Schmidt, L.S., Zbar, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Familial spontaneous pneumothorax. Chiu, H.T., Garcia, C.K. Current opinion in pulmonary medicine. (2006) [Pubmed]
  6. Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Schmidt, L.S., Warren, M.B., Nickerson, M.L., Weirich, G., Matrosova, V., Toro, J.R., Turner, M.L., Duray, P., Merino, M., Hewitt, S., Pavlovich, C.P., Glenn, G., Greenberg, C.R., Linehan, W.M., Zbar, B. Am. J. Hum. Genet. (2001) [Pubmed]
  7. Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability. Shin, J.H., Shin, Y.K., Ku, J.L., Jeong, S.Y., Hong, S.H., Park, S.Y., Kim, W.H., Park, J.G. J. Med. Genet. (2003) [Pubmed]
  8. A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M.L., Warren, M.B., Zbar, B., Schmidt, L.S., Hino, O. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Singh, S.R., Zhen, W., Zheng, Z., Wang, H., Oh, S.W., Liu, W., Zbar, B., Schmidt, L.S., Hou, S.X. Oncogene (2006) [Pubmed]
  10. Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Warren, M.B., Torres-Cabala, C.A., Turner, M.L., Merino, M.J., Matrosova, V.Y., Nickerson, M.L., Ma, W., Linehan, W.M., Zbar, B., Schmidt, L.S. Mod. Pathol. (2004) [Pubmed]
  11. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. Pavlovich, C.P., Grubb, R.L., Hurley, K., Glenn, G.M., Toro, J., Schmidt, L.S., Torres-Cabala, C., Merino, M.J., Zbar, B., Choyke, P., Walther, M.M., Linehan, W.M. J. Urol. (2005) [Pubmed]
  12. Kinetics and mechanism of the addition of benzylamines to benzylidene-3,5-heptadione in acetonitrile. Oh, H.K., Lee, J.M., Sung, D.D., Lee, I. J. Org. Chem. (2005) [Pubmed]
  13. Detection of 1733insC mutations in an Asian family with Birt-Hogg-Dubé syndrome. Kawasaki, H., Sawamura, D., Nakazawa, H., Hattori, N., Goto, M., Sato-Matsumura, K.C., Akiyama, M., Shimizu, H. Br. J. Dermatol. (2005) [Pubmed]
  14. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Toro, J.R., Glenn, G., Duray, P., Darling, T., Weirich, G., Zbar, B., Linehan, M., Turner, M.L. Archives of dermatology. (1999) [Pubmed]
  15. Expression of hypoxia inducible factor-1alpha and 2alpha in genetically distinct early renal cortical tumors. Kim, C.M., Vocke, C., Torres-Cabala, C., Yang, Y., Schmidt, L., Walther, M., Linehan, W.M. J. Urol. (2006) [Pubmed]
  16. Inactivation of BHD in sporadic renal tumors. Khoo, S.K., Kahnoski, K., Sugimura, J., Petillo, D., Chen, J., Shockley, K., Ludlow, J., Knapp, R., Giraud, S., Richard, S., Nordenskjöld, M., Teh, B.T. Cancer Res. (2003) [Pubmed]
  17. Enhanced soluble protein expression using two new fusion tags. Chatterjee, D.K., Esposito, D. Protein Expr. Purif. (2006) [Pubmed]
  18. Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome. Ubogy-Rainey, Z., James, W.D., Lupton, G.P., Rodman, O.G. J. Am. Acad. Dermatol. (1987) [Pubmed]
  19. Cancer-associated genodermatoses: a personal history. Burgdorf, W.H. Exp. Dermatol. (2006) [Pubmed]
  20. Birt-Hogg-Dubé syndrome and multinodular goitre. Drummond, C., Grigoris, I., Dutta, B. Australas. J. Dermatol. (2002) [Pubmed]
  21. Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules. Vincent, A., Farley, M., Chan, E., James, W.D. J. Am. Acad. Dermatol. (2003) [Pubmed]
  22. Free radicals and oxidative stress challenge dialysis patients: effects of two different membranes. Biasioli, S., Schiavon, R., Petrosino, L., Cavallini, L., Zambello, A., De Fanti, E., Giavarina, D. ASAIO journal (American Society for Artificial Internal Organs : 1992) (1997) [Pubmed]
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