| Written | 2007-02 | Laura S Schmidt |
| National Cancer Institute-Frederick, Frederick, MD 21702, USA |
| Identity |
| Alias_symbol (synonym) | BHD |
| MGC17998 | |
| MGC23445 | |
| Other alias | FLCL |
| Folliculin | |
| HGNC (Hugo) | FLCN |
| LocusID (NCBI) | 201163 |
| Atlas_Id | 789 |
| Location | 17p11.2 [Link to chromosome band 17p11] |
| Location_base_pair | Starts at 17221171 and ends at 17237188 bp from pter ( according to hg19-Feb_2009) [Mapping FLCN.png] |
| Fusion genes (updated 2016) | FLCN (17p11.2) / CCDC144CP (17p11.2) |
| Note | Putative tumor suppressor gene |
| DNA/RNA |
 | |
| Description | The FLCN/BHD gene consists of a 3717 nt mRNA (using NM_144997 derived from BQ423946 and AF517523, the coding sequence extends from nt499 to nt2238) and contains 14 coding exons. The initiation codon is located within exon 4. |
| Transcription | Northern blot analysis revealed a 3.8 kb FLCN/BHD mRNA transcript expressed in most tissues Alternate splicing of FLCN/BHD results in two transcript variants encoding two different isoforms. Transcript 1 is the full-length isoform. Transcript 2 has a shorter and distinct C-terminus from Transcript 1. |
| Protein |
| Description | The BHD protein, folliculin (FLCN), consists of 579 amino acids with a central glutamic acid-rich coiled-coil domain, one N-glycosylation site and three myristoylation sites, and an estimated molecular weight of 64.5 kDa. |
| Expression | expressed in most major adult tissues, including kidney, lung and skin, which are involved in the BHD phenotype. |
| Localisation | Epitope-tagged FLCN expressed in HEK293 cells localized in both the nucleus and cytoplasm by fluorescence in situ hybridization.. |
| Function | FLCN is a novel protein, with no characteristic domains to suggest function. Coimmunoprecipitation studies have identified a novel folliculin-binding partner, FNIP1, which also interacts with 5'AMP-activated protein kinase (AMPK), a key molecule for energy sensing and a negative regulator of mTOR (mammalian target of rapamycin). FLCN exists in phosphorylated forms, which are enhanced by FNIP1 overexpression, and suppressed by inhibitors of mTOR signaling including rapamycin and amino acid starvation, and by an AMPK inhibitor, Compound C. These data suggest that FLCN and its interacting partner, FNIP1, may be involved in energy and nutrient-sensing through the AMPK and mTOR signaling pathways. Using a genetic approach in Drosophila, RNA interference studies to decrease expression of the fly BHD homolog, DBHD, have established a requirement for DBHD in male germline stem cell maintenance in the fly testis. Further genetic studies to examine the interaction between DBHD and the JAK/STAT pathway, which is necessary for germline stem cell self-renewal, suggested that DBHD may regulate maintenance of germline stem cells downstream of or in parallel with the JAK/STAT and Dpp(a TGFbeta family member) signaling pathways. Thus the work with the Drosophila homolog of FLCN/BHD supports a potential role for DBHD in stem cell maintenance and raises the possibility that dysregulation of FLCN in human tumors may result from aberrant modulation of stem cells. |
| Homology | Folliculin shows no strong homology to any known proteins but is evolutionarily conserved, and orthologs have been identified in chimpanzee, dog, cow, rat, mouse, red jungle fowl, frog, fly, and worm. |
| Mutations |
| Germinal | All FLCN/BHD germline mutations identified in Birt-Hogg-Dubé (BHD) patients are predicted to truncate the mutant protein, including frameshift (insertions/deletions), nonsense and splice-site mutations. To date, no missense germline mutations have been identified. The mutation detection rate in BHD families is about 84%. 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 (BHD skin lesions, lung cysts/spontaneous pneumothorax and renal tumors). The most frequent mutation found in the germline of BHD patients is the insertion or deletion of a cytosine in a C8 tract located in exon 11, predicted to cause a frameshift and prematurely truncate the mutant protein. This hot spot mutation occurs in about half of all BHD patients. Among BHD patients with the exon 11 mutation, significantly fewer renal tumors developed in patients with the C-deletion than those with the C-insertion mutation. Germline FLCN/BHD mutations have been reported in primary spontaneous pneumothorax (PSP) families with nearly 100% penetrance in family members in which lung blebs or bullae indicated affected status. The PSP-associated mutations, including 2 nonsense and one 4-bp deletion, are predicted to prematurely truncate the protein and are located in exons 9, 12 and 4, respectively. |
| Somatic | 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%). |
| Implicated in |
| Note | |
| Entity | Birt-Hogg-Dubé syndrome |
| Disease | Birt-Hogg-Dubé(BHD) syndrome is an inherited autosomal dominant genodermatosis characterized by benign tumors of the hair follicle (fibrofolliculoma), lung cysts, spontaneous pneumothorax and renal neoplasia. Colon polyps or colon cancer may be part of the disease manifestations in some BHD cohorts although no statistically significant association was found. BHD syndrome is caused by germline mutations in the FLCN/BHD gene. Any or all of these phenotypic features may develop in a BHD patient; the phenotype is variable within and among BHD families inheriting the identical FLCN/BHD mutation (i.e., C-insertion/deletion in exon 11). |
| Prognosis | BHD is a rare disorder occurring in about 1/200,000 individuals. The BHD skin lesions, which develop after puberty (above 25 years of age) are highly penetrant (above 85%) and may be disfiguring, but they are benign and have no health consequences. Lung cysts detected by thoracic CT scan are very frequent (above 85%) in BHD patients. Episodes of spontaneous pneumothorax in BHD patients occur with a higher frequency before the age of 40, and repeat episodes cease after surgical intervention. The risk for developing renal neoplasia is about 7-fold higher for BHD mutation carriers than for their unaffected siblings. Most commonly, chromophobe renal carcinoma (34%) and oncocytic hybrid tumors (50%), develop in about half of BHD families with an average age at diagnosis of 48-50 and a male/female ratio of 2:1. Tumors may develop bilaterally with multiple foci or unilaterally with a single focus, and variable tumor histology may be seen in a single patient's kidney and among BHD family members carrying the same FLCN/BHD mutation. |
| Oncogenesis | Patients with BHD syndrome are at a higher risk for the development of chromophobe renal carcinoma, oncocytic hybrid renal tumors and clear cell renal carcinoma, which may be aggressive and metastatic. Renal oncocytosis, which are small clusters of cells resembling those found in the larger hybrid tumors, have been found scattered throughout the kidney of a majority of BHD patients, suggesting that the entire renal parenchyma may be at risk for tumor development. Second hit somatic mutations in the remaining wild type copy of the FLCN/BHD gene have been identified in renal tumors from BHD patients with germline mutations and may contribute to the progression of renal oncocytosis to renal neoplasia (see below). |
| Entity | Primary Spontaneous Pneumothorax (PSP) |
| Disease | Primary spontaneous pneumothorax is a condition in which air is present in the pleural space without a precipitating event that results in the secondary partial or complete collapse of the lung. FLCN/BHD mutations have been found associated with inherited autosomal dominant primary spontaneous pneumothorax (PSP) in some PSP families. In these families PSP was the only phenotypic feature and the mutation was 100% penetrant with lung bullae. |
| To be noted |
| Animal models of BHD: A germline single nucleotide insertion in the first coding exon of the rat Bhd ortholog was found in the Nihon rat, an established animal model of renal carcinoma, which develops renal tumors by 8 weeks of age. A germline mutation in the canine Bhd ortholog, which changes a conserved histidine to arginine (H255R), gives rise to RCND (renal cystadenoma nodular dermatofibroma) in the German Shepherd dog with a renal tumor and skin nodule phenotype. Tumor suppressor role for FLCN/BHD: Somatic mutations in the wild type copy of the FLCN/BHD gene or loss of heterozygosity at 17p11.2 have been identified in a majority of renal tumors from BHD patients who inherit germline mutations, suggesting that FLCN/BHD may act as a tumor suppressor gene. Tumors from a single BHD patient have different second mutations or LOH, but within the same tumor, even within regions with different histologies, the same second mutation was observed, suggesting that multiple tumors arise from independent, clonal events initiated by the second hit. Haploinsufficiency, however, may be sufficient for the development of the benign hair follicle tumors (fibrofolliculomas), because the wild type copy of the FLCN/BHD gene is retained in microdissected tissue from these skin lesions. |
| Bibliography |
| Birt-Hogg-Dubé syndrome: clinicopathologic findings and genetic alterations. |
| Adley BP, Smith ND, Nayar R, Yang XJ |
| Archives of pathology & laboratory medicine. 2006 ; 130 (12) : 1865-1870. |
| PMID 17149965 |
| 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 SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B |
| Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (42) : 15552-15557. |
| PMID 17028174 |
| A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome. |
| Bessis D, Giraud S, Richard S |
| The British journal of dermatology. 2006 ; 155 (5) : 1067-1069. |
| PMID 17034545 |
| Birt-Hogg-Dubé gene mutations in human endometrial carcinomas with microsatellite instability. |
| Fujii H, Jiang W, Matsumoto T, Miyai K, Sashara K, Ohtsuji N, Hino O |
| The Journal of pathology. 2006 ; 209 (3) : 328-335. |
| PMID 16691634 |
| Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. |
| Gad S, Lefèvre SH, Khoo SK, Giraud S, Vieillefond A, Vasiliu V, Ferlicot S, Molinié V, Denoux Y, Thiounn N, Chrétien Y, Méjean A, Zerbib M, Benoît G, Hervé JM, Allègre G, Bressac-de Paillerets B, Teh BT, Richard S |
| British journal of cancer. 2007 ; 96 (2) : 336-340. |
| PMID 17133269 |
| Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. |
| Graham RB, Nolasco M, Peterlin B, Garcia CK |
| American journal of respiratory and critical care medicine. 2005 ; 172 (1) : 39-44. |
| PMID 15805188 |
| Birt-Hogg-Dubé (BHD) gene mutations in human gastric cancer with high frequency microsatellite instability. |
| Jiang W, Fujii H, Matsumoto T, Ohtsuji N, Tsurumaru M, Hino O |
| Cancer letters. 2007 ; 248 (1) : 103-111. |
| PMID 16870330 |
| Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. |
| Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, Teh BT |
| Journal of medical genetics. 2003 ; 40 (7) : 511-515. |
| PMID 12843323 |
| Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. |
| Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjöld M, Teh BT |
| Oncogene. 2001 ; 20 (37) : 5239-5242. |
| PMID 11526515 |
| Clinical and genetic studies of Birt-Hogg-Dubé syndrome. |
| Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Lévy R, Ferlicot S, Wolkenstein P, Hammel P, Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjöld M, Richard S |
| Journal of medical genetics. 2002 ; 39 (12) : 906-912. |
| PMID 12471204 |
| Inactivation of BHD in sporadic renal tumors. |
| Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjöld M, Teh BT |
| Cancer research. 2003 ; 63 (15) : 4583-4587. |
| PMID 12907635 |
| A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. |
| Lingaas F, Comstock KE, Kirkness EF, S&oring;rensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA |
| Human molecular genetics. 2003 ; 12 (23) : 3043-3053. |
| PMID 14532326 |
| Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma. |
| Nagy A, Zoubakov D, Stupar Z, Kovacs G |
| International journal of cancer. Journal international du cancer. 2004 ; 109 (3) : 472-475. |
| PMID 14961590 |
| Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. |
| Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS |
| Cancer cell. 2002 ; 2 (2) : 157-164. |
| PMID 12204536 |
| 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 ML, Warren MB, Zbar B, Schmidt LS, Hino O |
| Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (7) : 2023-2027. |
| PMID 14769940 |
| A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. |
| Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomäki K |
| American journal of human genetics. 2005 ; 76 (3) : 522-527. |
| PMID 15657874 |
| Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. |
| Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, Linehan WM |
| The Journal of urology. 2005 ; 173 (5) : 1482-1486. |
| PMID 15821464 |
| Birt-Hogg-Dubé syndrome, a genodermatosis that increases risk for renal carcinoma. |
| Schmidt LS |
| Current molecular medicine. 2004 ; 4 (8) : 877-885. |
| PMID 15579035 |
| Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. |
| Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM |
| American journal of human genetics. 2005 ; 76 (6) : 1023-1033. |
| PMID 15852235 |
| Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability. |
| Shin JH, Shin YK, Ku JL, Jeong SY, Hong SH, Park SY, Kim WH, Park JG |
| Journal of medical genetics. 2003 ; 40 (5) : 364-367. |
| PMID 12746401 |
| 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 SR, Zhen W, Zheng Z, Wang H, Oh SW, Liu W, Zbar B, Schmidt LS, Hou SX |
| Oncogene. 2006 ; 25 (44) : 5933-5941. |
| PMID 16636660 |
| High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé renal tumors. |
| Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, Linehan WM |
| Journal of the National Cancer Institute. 2005 ; 97 (12) : 931-935. |
| PMID 15956655 |
| Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. |
| Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS |
| Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2004 ; 17 (8) : 998-1011. |
| PMID 15143337 |
| Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. |
| Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM |
| Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002 ; 11 (4) : 393-400. |
| PMID 11927500 |
| Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. |
| da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER |
| Journal of medical genetics. 2003 ; 40 (11) : 820-824. |
| PMID 14627671 |
| Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. |
| van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, Bladergroen RS, Steijlen PM, van Geel M |
| The Journal of investigative dermatology. 2007 ; 127 (3) : 588-593. |
| PMID 17124507 |
| Citation |
| This paper should be referenced as such : |
| Schmidt, LS |
| FLCN (folliculin gene) |
| Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):188-191. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/FLCNID789ch17p11.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
Kidney: Renal Oncocytoma
|
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Birt-Hogg-Dubé syndrome (BHDS) |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Tue Aug 1 17:26:32 CEST 2017 |
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