Folliculin is a protein found throughout the human body, playing a general role in cellular function. Its widespread presence in various tissues, including the brain, heart, lungs, and kidneys, suggests a broad involvement in maintaining normal physiological processes.
What is Folliculin?
Folliculin is a protein produced from instructions provided by the FLCN gene. This gene is located on the short arm of chromosome 17 at position 11.2. The FLCN gene consists of 14 exons and encodes a 64 kDa protein. It is broadly classified as a tumor suppressor, meaning it helps regulate cell growth and division.
Folliculin’s Role in Cellular Processes
Folliculin’s functions at the cellular level involve its participation in various signaling pathways that govern cell behavior. It forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2), which is involved in metabolic regulation. A significant aspect of folliculin’s role is its interaction with the mechanistic target of rapamycin complex 1 (mTORC1) pathway.
Folliculin acts as a GTPase-activating protein (GAP) for Rag C/D GTPases, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane. By influencing the Rag GTPases, folliculin helps regulate the translocation of mTORC1 to the lysosomal surface, where it becomes activated. This regulation of mTORC1 is important for sensing nutrient availability and controlling processes such as cell growth, metabolism, and energy homeostasis.
Beyond mTORC1, folliculin also interacts with AMP-activated protein kinase (AMPK), another key regulator of cellular metabolism. The loss of folliculin can lead to increased expression of PGC1α, which then results in elevated mitochondrial function and oxidative metabolism in renal cancer cells. This suggests folliculin plays a role in mitochondrial biogenesis and overall cellular energy management.
Birt-Hogg-Dubé Syndrome
Birt-Hogg-Dubé (BHD) syndrome is an inherited disorder directly linked to mutations in the FLCN gene. This condition is autosomal dominant, meaning a person only needs to inherit one copy of the mutated FLCN gene to develop the syndrome. The majority of these germline mutations are loss-of-function changes, such as frameshift or splice site mutations, which are predicted to result in an abnormally small or nonfunctional folliculin protein.
Individuals with BHD syndrome typically present with a combination of specific clinical manifestations. Skin lesions, known as fibrofolliculomas, are common benign tumors of the hair follicle that appear on the face, neck, and upper trunk. Lung cysts are another frequent finding, which can increase the risk of spontaneous pneumothorax, a condition where air leaks into the space between the lung and chest wall, causing lung collapse. While lung blebs are common in those with FLCN mutations, only about 40% experience a pneumothorax.
A serious manifestation of BHD syndrome is an increased risk of developing kidney tumors. These tumors are often multifocal, meaning multiple tumors can appear, and bilateral, affecting both kidneys. The kidney tumors associated with BHD syndrome typically include specific histological subtypes, such as chromophobe renal cell carcinoma and oncocytoma.
Living With and Researching BHD
Diagnosing Birt-Hogg-Dubé syndrome involves a combination of clinical evaluation and genetic testing. A healthcare provider will typically assess a person’s medical history and physical symptoms, looking for the characteristic skin lesions, a history of collapsed lungs, or kidney tumors. The definitive diagnosis often relies on genetic testing to identify a mutation in the FLCN gene.
Management strategies for individuals diagnosed with BHD syndrome focus on regular surveillance to detect and address potential complications early. This includes periodic imaging scans, such as abdominal MRI or CT scans, to monitor for the development or growth of kidney tumors. Regular chest imaging might also be recommended to check for lung cysts and assess the risk of pneumothorax. Management also involves surgical removal of kidney tumors when indicated, typically for larger or growing lesions.
Current research efforts are dedicated to deepening the understanding of BHD syndrome and finding new therapeutic approaches. Scientists are investigating the precise mechanisms by which folliculin dysfunction leads to tumor formation and cyst development. Efforts also include identifying new molecular targets for drug development that could help control cell growth in affected tissues or prevent tumor progression. These ongoing studies aim to improve patient outcomes and enhance the quality of life for individuals living with BHD syndrome.