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FLCN
folliculin
The FLCN gene encodes the folliculin protein, which is thought to function as a tumour suppressor, playing roles in cell growth, division, and tissue repair. The FLCN gene is responsible for producing the folliculin protein, which is found in many body tissues, including the kidneys, lungs, and skin.
FLCN is located on the short (p) arm of chromosome 17, at band 17p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The FLCN gene, also known as folliculin, provides the genetic blueprint for a protein of the same name. This protein is widely distributed throughout the body, found in tissues like the brain, heart, placenta, testes, skin, lungs, and kidneys. Although its exact functions are still being elucidated, folliculin is believed to act as a tumour suppressor, which are proteins that help control cell growth and division, preventing the uncontrolled proliferation that can lead to tumour formation.
Research indicates that folliculin may contribute to various cellular processes, including the uptake of foreign particles by cells, known as endocytosis or phagocytosis. It might also play a part in maintaining the cell's structural framework, or cytoskeleton, which is crucial for cell shape, size, and movement. Additionally, in the lungs, folliculin is thought to be involved in the repair and regeneration of lung tissue after damage.
What the gene does
The folliculin protein, encoded by the FLCN gene, is hypothesised to function primarily as a tumour suppressor. Tumour suppressor proteins are vital for regulating the cell cycle, preventing excessive cell growth and division. Although the specific molecular mechanisms are still being explored, research suggests that folliculin may influence several key cellular pathways.
Within cells, folliculin has been proposed to have a role in processes such as endocytosis, which is the mechanism by which cells internalise substances. It may also interact with the cytoskeleton, the intricate network of protein filaments that provides structural support and facilitates cellular movement. Furthermore, the protein is thought to be involved in cell-to-cell interactions. In the lung tissue specifically, folliculin is believed to contribute to the complex processes of tissue repair and regeneration following injury, highlighting its potential importance in maintaining tissue homeostasis.
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Chromosome location
The FLCN gene is situated on chromosome 17, specifically at position 17p11.2. This genomic location refers to the short (p) arm of chromosome 17, in region 1, band 1, sub-band 2. The precise positioning of the gene on the chromosome helps in mapping its physical location and understanding its relationship to other genes in the human genome.
Protein structure
The folliculin protein is composed of 579 amino acids. Its structural organisation includes several distinct domains and regions that are crucial for its function. An N-terminal Disordered region is located between amino acids 30 and 81. Following this, the uDENN FLCN/SMCR8-type domain spans amino acids 86 to 242. Within this domain, a specific region essential for interaction with LDHA is identified between amino acids 210 and 220. Further along the protein, a Coiled coil motif is found from amino acids 287 to 310, followed by another Disordered region from amino acids 294 to 337. The central part of the protein contains the cDENN FLCN/SMCR8-type domain, ranging from amino acids 339 to 491. Finally, a dDENN FLCN/SMCR8-type domain is present towards the C-terminus, from amino acids 493 to 558.
Key variants
Variants within the FLCN gene can alter the normal function of the folliculin protein. These changes may involve substitutions of single amino acids, insertions, or deletions of larger segments of the protein's genetic code. Such alterations can lead to the production of a truncated, non-functional protein or impair its ability to interact with other cellular components. The clinical impact of these variants can range significantly, from mild to severe, depending on the specific change and its effect on protein activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1301_1302del | - | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1014del | p.Trp338fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1015C>T | p.Gln339Ter | Pathogenic | ★★☆☆ | Birt-Hogg-Dube syndrome |
c.1021del | p.Arg341fs | Pathogenic | ★★☆☆ | Birt-Hogg-Dube syndrome |
c.1036_1043del | p.Phe346fs | Pathogenic | ★★☆☆ | Birt-Hogg-Dube syndrome |
c.1038dup | p.Lys347fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1062+1G>A | - | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1062+2T>G | - | Pathogenic | ★★☆☆ | not provided |
c.1063-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Birt-Hogg-Dube syndrome |
c.1098_1102dup | p.Val368fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the FLCN gene are primarily associated with an inherited condition called Birt-Hogg-Dubé syndrome. This syndrome is characterised by the development of multiple benign skin tumours, an increased risk of specific internal tumours, and the formation of lung cysts. Additionally, FLCN gene variants have been linked to primary spontaneous pneumothorax, a condition where air abnormally accumulates between the lung and chest wall, potentially causing lung collapse.
Inheritance pattern
Conditions caused by pathogenic FLCN variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The FLCN gene is included in several active UK NHS national genomic testing panels, indicating its clinical significance within the UK healthcare system. It is covered under panels for Adult solid tumours cancer susceptibility, Adult solid tumours for rare disease, Cystic kidney disease, and Inherited renal cancer (R224). Additionally, FLCN is part of the Multiple monogenic benign skin tumours (R230), Pneumothorax - familial (R190), Renal cancer pertinent cancer susceptibility, and Thoracic aortic aneurysm or dissection panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle can generally support overall well-being, though there is no conclusive evidence that specific lifestyle interventions can prevent conditions associated with FLCN gene variants. Research suggests that a balanced diet rich in fruits, vegetables, and whole grains, combined with regular physical activity, contributes to general health. Avoiding smoking and excessive alcohol consumption is widely recommended for reducing the risk of various health issues, including those affecting the lungs and kidneys.
Supplement considerations
There is no scientific evidence to suggest that taking specific dietary supplements can prevent or treat conditions associated with FLCN gene variants. Individuals considering supplements should consult a healthcare professional. Any claims regarding supplements preventing inherited conditions are not supported by robust clinical data and should be approached with caution.
Frequently asked questions
What is the FLCN gene?
The FLCN gene provides instructions for making the folliculin protein, which is believed to act as a tumour suppressor. This protein helps regulate cell growth and division and is found in many body tissues.
What conditions are associated with FLCN gene variants?
Pathogenic variants in the FLCN gene are primarily associated with Birt-Hogg-Dubé syndrome, an inherited condition characterised by benign skin tumours, lung cysts, and an increased risk of certain internal tumours. It has also been linked to primary spontaneous pneumothorax.
How does the folliculin protein function?
The folliculin protein is thought to be a tumour suppressor, helping to control cell proliferation. It may also be involved in cellular processes like endocytosis, maintaining the cytoskeleton, cell-to-cell interactions, and tissue repair, particularly in the lungs.
Is the FLCN gene included in UK NHS genomic testing?
Yes, the FLCN gene is part of several active UK NHS national genomic testing panels. These include panels for various solid tumours, kidney conditions, and familial pneumothorax.
Can lifestyle changes prevent conditions linked to FLCN gene variants?
While a healthy lifestyle generally supports overall well-being, there is no definitive evidence that specific lifestyle changes can prevent or alter the course of inherited conditions associated with FLCN gene variants. Always discuss lifestyle choices with a healthcare provider.
References
- Fröhlich BA, Zeitz C, Mátyás G. Novel mutations in the folliculin gene associated with spontaneous pneumothorax. The European respiratory journal. 2008. PMID: 18579543
- Painter JN, Tapanainen H, Somer M. A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. American journal of human genetics. 2005. PMID: 15657874
- Graham RB, Nolasco M, Peterlin B. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. American journal of respiratory and critical care medicine. 2005. PMID: 15805188
- Schmidt LS, Nickerson ML, Warren MB. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics. 2005. PMID: 15852235
- Vocke CD, Yang Y, Pavlovich CP. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute. 2005. PMID: 15956655
- Warren MB, Torres-Cabala CA, Turner ML. Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2004. PMID: 15143337
- Shin JH, Shin YK, Ku JL. Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability. Journal of medical genetics. 2003. PMID: 12746401
- Kahnoski K, Khoo SK, Nassif NT. Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. Journal of medical genetics. 2003. PMID: 12843323
- da Silva NF, Gentle D, Hesson LB. Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. Journal of medical genetics. 2003. PMID: 14627671
- Nickerson ML, Warren MB, Toro JR. 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. Cancer cell. 2002. PMID: 12204536