FLCN (folliculin gene)

2007-02-01   Laura S Schmidt 

National Cancer Institute-Frederick, Frederick, MD 21702, USA

Identity

HGNC
LOCATION
17p11.2
LOCUSID
ALIAS
BHD,DENND8B,FLCL
FUSION GENES

DNA/RNA

Atlas Image

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.

Proteins

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 5AMP-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

Entity name
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 patients 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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
171499652006Birt-Hogg-Dubé syndrome: clinicopathologic findings and genetic alterations.Adley BP et al
170281742006Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.Baba M et al
170345452006A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome.Bessis D et al
166916342006Birt-Hogg-Dubé gene mutations in human endometrial carcinomas with microsatellite instability.Fujii H et al
171332692007Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma.Gad S et al
158051882005Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults.Graham RB et al
168703302007Birt-Hogg-Dubé (BHD) gene mutations in human gastric cancer with high frequency microsatellite instability.Jiang W et al
128433232003Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours.Kahnoski K et al
115265152001Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2.Khoo SK et al
124712042002Clinical and genetic studies of Birt-Hogg-Dubé syndrome.Khoo SK et al
129076352003Inactivation of BHD in sporadic renal tumors.Khoo SK et al
145323262003A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.Lingaas F et al
149615902004Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma.Nagy A et al
122045362002Mutations 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 et al
147699402004A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.Okimoto K et al
156578742005A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax.Painter JN et al
158214642005Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome.Pavlovich CP et al
155790352004Birt-Hogg-Dubé syndrome, a genodermatosis that increases risk for renal carcinoma.Schmidt LS et al
158522352005Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.Schmidt LS et al
127464012003Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.Shin JH et al
166366602006The 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 et al
159566552005High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors.Vocke CD et al
151433372004Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues.Warren MB et al
119275002002Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.Zbar B et al
146276712003Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer.da Silva NF et al
171245072007Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients.van Steensel MA et al

Other Information

Locus ID:

NCBI: 201163
MIM: 607273
HGNC: 27310
Ensembl: ENSG00000154803

Variants:

dbSNP: 201163
ClinVar: 201163
TCGA: ENSG00000154803
COSMIC: FLCN

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000154803ENST00000285071Q8NFG4
ENSG00000154803ENST00000389169Q8NFG4
ENSG00000154803ENST00000389169A0A0S2Z5Y7
ENSG00000154803ENST00000417064C9J4C4
ENSG00000154803ENST00000461699J3QQZ7

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
mTOR signaling pathwayKEGGko04150
Renal cell carcinomaKEGGko05211
mTOR signaling pathwayKEGGhsa04150
Renal cell carcinomaKEGGhsa05211

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
122045362002Mutations 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.214
240952792013The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1.186
170281742006Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.152
182347282008BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.114
158522352005Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.104
159566552005High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors.78
192345172009The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis.77
247624382014The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation.56
229777322012Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer.52
124712042002Clinical and genetic studies of Birt-Hogg-Dubé syndrome.51

Citation

Laura S Schmidt

FLCN (folliculin gene)

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/gene/789/flcn-(folliculin-gene)