FLCN

The FLCN gene encodes folliculin, a tumor suppressor protein that helps regulate cell growth, energy balance, and autophagy through pathways like mTOR and AMPK. 

Mutations in FLCN are most notably linked to Birt-Hogg-Dubé syndrome, a genetic condition that increases the risk of kidney tumors, lung collapse, and characteristic skin growths.

What is FLCN (Folliculin)?

The FLCN gene provides instructions for making folliculin, a protein that plays a key role in regulating cell growth, energy balance, and tumor suppression. Located on chromosome 17p11.2, FLCN is active in many tissues, including the skin, lungs, kidneys, brain, and heart.

Folliculin does not contain traditional functional domains but forms a complex with FNIP1 and FNIP2, which connect it to major metabolic pathways such as mTOR and AMPK. 

It also helps regulate processes like autophagy, lysosomal function, and cell adhesion.

FLCN: A Tumor Suppressor Gene

FLCN is best known for its role as a tumor suppressor. It helps prevent abnormal cell growth and division. When the FLCN gene is mutated, cells can grow out of control, potentially leading to tumors or cyst formation, particularly in the kidneys, lungs, and skin.

FLCN Gene and Protein

The FLCN gene provides instructions for making a protein called folliculin.

Folliculin plays a multifaceted role in cellular metabolism, intracellular signaling, and maintaining cell structure. It regulates the mTORC1 pathway, which is essential for controlling cell growth and survival, and interacts with AMPK, a critical energy sensor that helps cells respond to metabolic stress. 

Folliculin also represses the activity of the transcription factors TFEB and TFE3, which are involved in autophagy and lysosomal function. 

Additionally, it influences epidermal growth factor receptor (EGFR) trafficking, contributes to the maintenance of cell polarity, and regulates cell-to-cell junctions.

Cellular Functions of Folliculin

While the exact function of folliculin is still being studied, it is known to play an essential role in:

• mTOR signaling: Regulates cell growth and nutrient sensing
• Autophagy: Helps cells remove damaged or unnecessary components
• Energy metabolism: Works with AMPK to adjust to cellular energy needs
• Cell adhesion: Maintains healthy tissue structure, especially in the lungs
• Endosomal trafficking: Helps degrade proteins like EGFR through lysosomes

FLCN and Associated Disorders

The following conditions are associated with FLCN mutations:

Birt-Hogg-Dubé Syndrome (BHD)

Mutations in FLCN cause Birt-Hogg-Dubé syndrome (BHD), a rare inherited condition. BHD is autosomal dominant, meaning a mutation in just one copy of the gene is enough to cause disease.

The main features of BHD include:

• Skin lesions:
  
  • Called fibrofolliculomas, usually on the face, neck, and upper trunk
  • Develop in over 85% of patients, often by age 25
• Lung cysts and spontaneous pneumothorax:
  
  • Up to 75% of patients have lung cysts
  • About 25–50% experience a collapsed lung, often by age 40
• Kidney tumors:
  
  • Occur in up to 30% of individuals with BHD
  • Most common types: chromophobe renal cell carcinoma (RCC) and hybrid oncocytic tumors
  • Usually bilateral (affecting both kidneys), multifocal, and slow-growing
  • Renal cancer risk is 7x higher in BHD than in the general population
• Other findings (less common): renal cysts, thyroid nodules, parotid tumors, and lipomas.

When is FLCN Genetic Testing Relevant?

Genetic testing for FLCN mutations is recommended for:

Individuals with Symptoms of BHD

Individuals with symptoms of BHD should consider genetic testing for FLCN mutations:

• Multiple characteristic skin lesions
• Recurrent spontaneous pneumothorax
• Kidney tumors, especially chromophobe or hybrid types

Individuals with a Family History of BHD

Patients with a family history of BHD may consider genetic testing, especially for family planning. 

Families with a History of Early-Onset Kidney Cancer or Lung Collapse

Families with a history of early-onset kidney cancer or spontaneous lung collapse should be evaluated for FLCN mutations, as these are hallmark features of Birt-Hogg-Dubé syndrome.

What Do Specific FLCN Mutations Mean?

Pathogenic mutations in the FLCN gene—most commonly nonsense, frameshift, or splice-site variants—confirm a diagnosis of Birt-Hogg-Dubé (BHD) syndrome. Because BHD follows an autosomal dominant inheritance pattern, a single pathogenic variant is sufficient to cause the condition. 

Some missense mutations may result in partial or variable loss of function, adding to the complexity of disease expression. Notably, there is often significant variability in symptoms even among individuals within the same family, a phenomenon known as variable expressivity. 

In kidney tumors associated with BHD, loss of heterozygosity (LOH) is frequently observed, further supporting FLCN's critical role as a tumor suppressor.

What Does the Absence of Pathogenic FLCN Mutations Mean?

A negative test does not rule out BHD or related disorders; other genetic or environmental factors may still explain similar symptoms. 

If suspicion remains high, additional testing (e.g., whole-exome sequencing or copy number analysis) may be needed.

Genetic counseling is highly recommended to interpret test results and guide the next steps.

Test Procedure and Interpretation

Testing for FLCN is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FLCN genetic testing are considered to be without mutations that can alter the activity of the FLCN proteins.

Clinical Implications of Positive FLCN Mutations

The clinical implications of a positive FLCN mutation test result will vary by individual, although FLCN mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms associated with muscle and nervous system symptoms.

Patients or practitioners with questions about the clinical implications of FLCN mutations should seek further assessment with a genetic counselor or expert. 

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