BHD Case Reports: Summer Round-Up

Every few months we like to highlight some of the recent case reports of Birt-Hogg-Dubé syndrome (BHD). A case report is a detailed account of (normally) a single person’s diagnosis and treatment journey. In this blog, we present 3 cases of BHD and cancer.

A case of two types of kidney cancer

In this case report, a 36-year-old woman underwent an MRI scan which showed she had two tumours in her left kidney. She had surgery to remove the tumours. Samples were taken from the tumours to confirm what kind of cancer she had. One of the tumours was confirmed to be clear cell kidney cancer and the other was chromophobe kidney cancer. Genetic testing showed a mutation in the gene folliculin (FLCN), the gene associated with BHD. It turned out that the patient also had a history of collapsed lungs but did not have any skin bumps. Multiple members of her family also had lung cysts, but they did not consent to genetic testing.

This case is interesting due to the tumours being different types of kidney cancer. It highlights the complex nature of BHD and the need for a better understanding of the different types of kidney cancer linked with BHD as well as how BHD causes kidney cancer.

A case of BHD with only kidney symptoms

In this report*, a 51-year-old woman with breast cancer had a CT scan of her chest and stomach to help stage her breast cancer. She was found to have several tumours in both her kidneys. They took a sample of the tumour to confirm they were not caused by her breast cancer spreading. At the time, BHD was not suspected due to the lack of skin symptoms and no family history of any BHD symptoms. The patient received treatment for her breast cancer and soon after had surgery to remove her kidney tumours. In total, 12 tumours were removed, and they were all confirmed to be hybrid oncocytic/chromophobe tumours. Although much of the kidney was preserved, this did slightly reduce her kidney function. This diagnosis prompted further investigation for BHD. Genetic testing showed a mutation in FLCN, c.602A>C, that has not previously been reported (see our guide on understanding genetic sequencing results for more information). The same mutation was also found in the patient’s mother who did not have any symptoms of BHD. The patient also had no other symptoms of BHD.

This report highlights one of the few instances of BHD with only kidney symptoms. Currently, it is unclear if only kidney symptoms can be linked to particular FLCN mutations.

BHD and testicular cancer

In this case report* a 34-year-old male presented to the clinic with a history of skin bumps on the face, neck and chest. The patient had also had 2 collapsed lungs which required a pleurodesis. A review of his family history showed that multiple members had similar skin symptoms. There was also a family history of skin cancer (melanoma). Genetic testing confirmed a mutation in FLCN confirming the diagnosis of BHD. Of interest, the patient also had a left-sided testicular seminoma (a type of cancer) at the age of 29. Then at the age of 34, he was found to have a right-sided testicular seminoma. Both were treated by surgery.

Testicular cancer has only been reported in BHD once before, however that individual also had neurofibromatosis type 1 (NF1). The authors of the previous report could not conclude if this was linked to BHD, NF1 or was just a coincidental finding as testicular cancer is a common cancer among men aged 15-34 years. However, this type of cancer has been previously linked to the same molecular pathway as FLCN. Due to this patient having cancer in both testicles at different times, the authors of this case report suggest that the association needs further investigation. Given that this is only the 2nd report of testicular cancer in BHD, if there is any association it appears to be extremely rare.

Summary

These three case reports highlight the need for a better understanding of BHD. Although case reports are useful for revealing possible conditions associated with BHD, a larger sample of people is needed to confirm whether they are linked. This is one of the reasons why we launched the BHD Syndrome International Registry earlier this year. We need a centralised database to collect this information on a global scale to drive forward research and find new treatments or even a cure for BHD.

*Please note these papers are unfortunately not freely available.

How Common is BHD? A Study in a Healthcare System Population

The prevalence of Birt-Hogg-Dubé syndrome is currently unknown. Some reports have estimated the prevalence to be 1 in 200,000 people, but this is likely an underestimate of the true figure. There have been multiple reports looking at how common BHD-related features are. For example, it is thought that:

•             around 9 in 10 people develop skin bumps.

•             around 1 in 4 people will have a collapsed lung.

•             up to 1 in 3 people will get kidney cancer.

These figures can be biased based on multiple factors. For example, a study carried out in a lung centre may find that lung symptoms are more common. This is often due to the underlying bias that most individuals who are seeing a lung doctor have lung problems. The demographics of the population being studied is also important as there have been differences in the symptoms reported in different ethnicities. Understanding the true prevalence of BHD is important as it will influence the counselling and future management of the condition.

A recent paper has estimated the prevalence of BHD. One of the best ways to do this is to look at how many people have a mutation in the gene associated with BHD, folliculin (FLCN) The authors looked at FLCN variants in a specific healthcare system-based population in Pennsylvania. They then went on to estimate how many people with a FLCN variant had any symptoms using electronic health records (EHR).

They found a FLCN variant in 35 people out of 135,990 people tested (1 in 3885 people). This is very different to the previously estimated 1 in 200,000 people. However, the 35 individuals came from 28 different families in the cohort.When this was taken into account,the prevalence of FLCN variants increased to 1 in 3234 people. A total of 13 unique FLCN variants were identified, 9 of which had been reported previously. It should be noted that the authors only look for pathogenic or likely pathogenic FLCN variants. When the authors looked at the EHR of the 35 people, 24 of them had at least one BHD-related feature documented.

Skin

21 people had seen a dermatologist and/or had a skin biopsy performed. However, only 3 out of 21 people had a BHD-related skin finding. This is in contrast to the literature which reports a high number of skin symptoms among people with BHD. The authors did not suggest why there was a lower frequency of skin symptoms reported in this study.

Lung

23 out of 35 people had lung symptoms. However, only 29 of 35 people had a CT or MRI scan that included at least part of the lungs. Lung cysts were confirmed in 23 out of 29 people. However, only 13 of these had scans in which the entirety of the lungs could be visualised. Of these, all 13 had lung cysts. It is possible that lung cysts were missed in people who did not have a lung scan or partial lung scan. 6 out of 23 people had experienced at least one collapsed lung. 4 people had repeated instances of collapsed lungs.

Kidney

Only 1 person was found to have kidney cancer (chromophobe renal cancer). Of the remaining 34 people with a FLCN variant, 27 had imaging that included the kidneys. Of these, 23 had imaging that showed the entire kidneys. 3 people had renal masses, however these had not been confirmed to be kidney cancer or associated with BHD.

Other symptoms

The authors also reviewed the EHR of the individuals to determine if they were any other BHD-related features. They noted one case of parotid oncocytoma. No individuals had thyroid cancer and they did not report on colon cancer.

Diagnosis

Only 4 of the 35 people had a diagnosis of BHD in their EHR. All 4 had at least one BHD-related symptom, including lung cysts. The authors comment on the fact that although 23 people had lung cysts, this did not warrant further investigation such as referral for genetic testing. Additionally, lung cysts in the 9 of 23 people were only found on review of the data by a radiologist and were not originally documented in the EHR. Improved clinical recognition of seemingly harmless signs such as lung cysts is needed. Recognising these features should prompt additional evaluation for an underlying genetic cause. Early diagnosis of BHD is important for the management of the condition to identify and treat any kidney cancer as soon as possible. It may also influence treatment of other BHD symptoms such as collapsed lungs. A pleurodesis may be performed earlier in people with BHD to prevent recurrent episodes of lung collapses.

Summary

The authors of this study found 1 in 3234 people with a FLCN variant in their healthcare system-based population. When considering symptoms, 1 in 5663 individuals had a FLCN variant and at least one BHD-related feature. In this study, only 4 out of 35 individuals were diagnosed with BHD. The authors noted some limitations to their current study. Firstly, most individuals in the cohort are of European ancestry and from the same healthcare system. It is therefore unclear if the findings in this study can be generalised across different populations. Secondly, the estimates of the frequency of symptoms in this study were dependent on data found within the EHR. For example, not every individual had sufficient imaging done to fully assess the symptoms. This further highlights the need to raise awareness of BHD among healthcare professionals to aid early diagnosis.

European Conference on Rare Diseases 2022: Report

We were delighted to attend the 11th European Conference on Rare Diseases & Orphan Products 2022 which was held from 27th June to 1st July. Over 840 participants from 61 countries came together with the goal of improving the quality of life of those with rare conditions. Although there are thousands of rare diseases, collectively they can be thought of as common. It is critical for our voices to be heard and represent the rare disease community to drive change.  

Patient Data 

The event discussed the use of patient data in research. It was stressed that the use of any patient data must lead to a direct impact on the patients themselves. It was also highlighted that research and healthcare need to be interlinked. For example, generating real world evidence through the use of patient registries is an important aspect of driving research. However, using patient health data to inform changes in healthcare policy is also critical. Better integration of patient health data into healthcare systems is needed.  

Journey to Diagnosis 

The importance of early diagnosis was also featured at the event. Some initial results from the Global Rare Barometer Survey were presented. This survey ran from March to June 2022 and had 13000 respondents from around the world. The results showed there were many barriers and delays to being diagnosed. These included a lack of awareness at the primary care level and a lack of coordination of care. The task of finding doctors also often fell on the patient. The solutions to these problems are not simple. It is impossible for doctors to be aware of every rare condition. Instead, they need to be educated on how to find the right information to help a patient. Management of rare conditions could also be improved through the creation of centres of expertise. These could coordinate the care a patient requires.  

BHD Syndrome International Registry 

Katie Nightingale, Charity Officer at the BHD Foundation and Myrovlytis Trust, presented her work developing the BHD Syndrome International Registry (BIRT). This poster has been approved and published at the European Conference on Rare Disease & Orphan Products 2022 and republished here with their permission.  

BIRT is needed to generate high quality patient data that can drive forward research. The overall aims are to: 

  • Improve quality of life for BHD patients. 
  • Facilitate faster diagnoses and reach a consensus on diagnosis and management guidelines. 
  • Help develop treatments or a cure for BHD. 

Anyone with BHD can take part in the registry and help to advance research into BHD.  

We were delighted to be able to join the conference and present our work. We would like to thank the organisers of the conference for hosting such a thought-provoking event. We are committed to improving the quality of life of those with Birt-Hogg-Dubé syndrome. We look forward to what the future holds for improving diagnosis, care and treatment of rare diseases.

What is the difference between BHD and LAM?

Today (June 30th) is World Pneumothorax Day. We are coming together to raise awareness of the inherited (familial) causes of collapsed lungs. Around 1 in 10 lung collapses have a genetic cause. Early and accurate diagnosis of the cause of familial pneumothorax is important. There are many different conditions associated with collapsed lungs. They often have other symptoms that need to be managed.

Birt-Hogg-Dubé Syndrome (BHD) is the most common genetic cause of collapsed lungs, where a diagnosis can be made. BHD is associated with mutations in the gene folliculin (FLCN). BHD can cause:

  • Skin bumps called fibrofolliculomas
  • Lung cysts and collapsed lungs
  • Kidney cancer

Another condition associated with collapsed lungs is lymphangioleiomyomatosis (LAM). LAM is a rare condition caused by mutations in the tuberous sclerosis genes. It affects the lungs, kidneys and lymphatic system. The most common symptom of LAM is shortening of breath that gets worse over time. LAM almost exclusively occurs in women.

As BHD and LAM can have similar symptoms, the two can commonly be confused. We spoke to Professor Nishant Gupta to find out more about LAM and BHD. Professor Gupta is Director of the Interstitial Lung Diseases Center, University of Cincinnati.

What are the main similarities and differences between BHD and LAM?

Both BHD and LAM can present with air-filled pockets in the lungs called cysts. These cysts are prone to rupture frequently leading to lung collapse (pneumothorax). While both BHD and LAM can have kidney symptoms, the type of symptoms differ. People with BHD tend to have multiple different types of kidney tumours. However, people with LAM tend to have benign (non-cancerous) fatty tumours called angiomyolipomas.

The lung disease in LAM can progress over time while the lung disease in BHD generally doesn’t tend to be severe or progressive. Patients with BHD can also have (benign) skin tumours (fibrofolliculomas). Skin tumours are typically not seen in patients with LAM unless LAM is associated with the inheritable syndrome called Tuberous Sclerosis Complex (TSC).

How is each condition diagnosed and why are some people misdiagnosed?

The fact that both diseases can cause lung cysts and present with lung collapses often leads to misdiagnosis. Critical review of the chest CT scan is very important and can often provide clues to distinguish between BHD and LAM. For instance, cysts in LAM tend to be round, uniform, and present in all areas of the lung. In contrast, cysts in BHD tend to be oval and have varying sizes. They are more commonly seen at the bottom of the lungs often close to the lung linings (pleura) and blood vessels.

Personal and/or family history of skin bumps, collapsed lungs, and kidney tumours can also provide a clue towards underlying BHD. The diagnosis of BHD can be strongly suggested by confirming the skin lesions are fibrofolliculomas. This can be confirmed with genetic testing. Lung biopsy is not helpful to diagnose BHD.

The diagnosis of LAM can be established based on one or more of these features in a patient with compatible chest CT scan:

  • presence of underlying TSC
  • renal angiomyolipomas
  • elevated blood values of a protein called vascular endothelial growth factor-D (VEGF-D)
  • lymphatic involvement such as chylous (milky) fluid collections (e.g. in the chest cavity).

One or more of these features are present in approximately 7 in 10 people with LAM. In the remaining people, a lung biopsy may be needed to confirm the diagnosis of LAM.

How is each condition managed?

From a lung standpoint, both diseases predispose people to the development of collapsed lungs. Individuals who have one lung collapse have a very high chance of having repeat episodes. It is recommended that people with LAM and BHD undergo procedures such as pleurodesis following the first lung collapse. This can help to reduce the risk of future lung collapses. Beyond the risk of collapsed lungs, the lung disease in BHD generally is not severe or progressive. It doesn’t normally need any specific treatment. In contrast, the lung disease in LAM can be progressive and may require treatment with a drug called sirolimus. This has been shown to stabilize lung function decline and improve quality of life in LAM.

What should a person do if they think they may have BHD or LAM?

People with suspected BHD or LAM should see a physician who is familiar with these disorders. Detailed history, physical examination and critical review of the chest CT scan can often provide a good idea of the likely answer. It is important to note that there are other conditions that can cause lung cysts beyond BHD and LAM. Some of these may be diagnosed based on family history and blood work (for example, autoimmune diseases such as Sjögren’s). There is a worldwide network of lung physicians interested in rare lung diseases such as BHD and LAM. They can help patients navigate through the right diagnosis and management pathway:

USA: https://thelamfoundation.org/Healthcare-Providers/Diagnosis-Treatment/US-LAM-Clinics

Rest of the world: https://thelamfoundation.org/Healthcare-Providers/Diagnosis-Treatment/International-LAM-Clinics

What is the focus of your research?

My research is focused on rare cystic lung diseases such as LAM and BHD including:

  • Improving the understanding of the natural history of disease progression.
  • Devising novel ways to monitor disease progression.
  • Exploring new biomarkers and treatment options.
  • Helping answer questions that are relevant to the daily lives of patients living with these conditions.

What do you hope for the future of BHD and LAM?

My long-term hope for both diseases is the development of a cure. My short-term hope is for us to be able to reduce the time it takes for some patients to get diagnosed. It is also important to establish the diagnosis in a non-invasive manner as much as possible. I hope we can devise blood-based biomarkers that can help distinguish between these diseases. In LAM, this would remove the need for invasive procedures such as lung biopsies. Improved means of pleurodesis and other management strategies is another aspect that needs to be improved. This would reduce the burden of lung collapses in both sets of patients.

There are lots of common themes that are relevant to both conditions. I hope our scientific and patient communities can work together to accelerate the progress in both LAM and BHD.

The BHD Foundation sincerely thanks Professor Gupta for taking part in this interview and sharing his expertise on LAM and BHD. The LAM Foundation have many great resources to help people diagnosed with LAM.

Married on a Mountain with a Collapsed Lung

Joanna got married 7500ft above sea level at the top of a mountain. She didn’t realise the pain in her shoulder was her lung collapsing and that she had a rare condition called Birt-Hogg-Dubé (BHD) syndrome.

We have partnered with Rare Revolution to tell her incredible and inspirational story and raise awareness of the rare causes of pneumothorax.

You can also watch her story below:
Video Transcript

BHD Syndrome at a Rare Lung Disease Clinic in China 

The first study of Birt-Hogg-Dubé Syndrome (BHD) in China was published in 2008. However, by the end of 2021 there were still only 221 Chinese patients reported in the literature. Given the large population of China, it is very likely that BHD is highly underdiagnosed. In 2019, a Rare Lung Disease Clinic was set up at The First Affiliated Hospital of USCT in Anhui province, China. The aim of the clinic was to improve the diagnosis and management of patients with rare lung diseases including BHD. 

Clinical Features 

This recent study highlights the clinical and genetic features of 50 people from 31 families diagnosed with BHD from January 2017 to December 2021. The average age at diagnosis was 47.4 years (ranging from 18 to 76 years of age). The clinical features of these patients were as follows (please note that not every individual underwent every scan or examination): 

  • 48 out of 49 people had lung cysts. 
  • 27 out of 50 people had at least one collapsed lung. 
  • 29 out of 50 people reported a family history of collapsed lungs. 
  • 32 out of 47 people had skin symptoms defined as multiple, skin-coloured papules.  
  • 2 out of 41 people had kidney cancer. 
  • 4 out of 41 people had a type of non-cancerous kidney tumour called angiomyolipoma. 

Focusing on the lung symptoms in more detail, it was reported that the average number of collapsed lungs a person had was 2. The maximum number an individual had was 7. There were 3 episodes of lung collapses on both lungs at the same time (bilateral). Lung cysts were the most common sign. Most people had more than 20 cysts in both lungs which ranged between 1 and 5 cm and were irregular in shape. In all cases, the cysts were found towards the bottom of the lungs, a typical feature of BHD.  

Of interest, this is one of the few reports from East Asia which reports a high number of people with skin symptoms. However, only 9 people underwent a biopsy to confirm the type of skin manifestation. 2 were reported to be fibrofolliculomas. 1 was confirmed as a trichodiscoma and the others were confirmed to be epidermoid cysts. The authors of the study discussed the differences seen in their study compared with other studies. They suggested that the skin symptoms may have been overlooked previously. Evidence shows these are increasing reported in newer studies. 

The authors also note the low incidence of kidney cancer in this group. They comment that this may be due to selection bias since nearly everyone in the study was recruited through the rare lung disease clinic and not a kidney clinic. However, they also do not exclude the role genetics may play. The low incidence of kidney cancer in East Asian BHD patients has been reported before.  

Genetics 

45 individuals underwent genetic testing for BHD (the rest were diagnosed clinically). Of these 45 people, a mutation in folliculin (FLCN) was found in 44. The most common mutations were c.1285dup, c.1285del, which are generally the most reported FLCN mutations. Find out more about understanding genetic mutations here

Management of BHD 

The authors compared the recurrence rate of collapsed lungs between those who had surgery and those who had a more conservative treatment (e.g. a chest drain). Reoccurrence was more common in people who had chest drains.   
Only 15 patients underwent annual follow-up in the study. The authors discussed that this could also contribute to the low incidence of kidney cancer seen. Ideally, people with BHD should get regular kidney scans so that any kidney cancer can be found and treated quickly.  

Summary 

This study represents, so far, the largest cohort of individuals with BHD in the Chinese population. Although lung symptoms were still the most reported, there was a high number of individuals with skin symptoms. The Rare Lung Disease Clinic is a multidisciplinary team made up of different specialists. These include a radiologist, pathologist, dermatologist, urologist and thoracic surgeon, as well as lung specialists. You can read more about the different types of healthcare professionals here. The authors state their multidisciplinary approach is the best for the diagnosis and management of BHD. They saw an increase in the number of people diagnosed with BHD year on year after establishing the clinic. In the future, the authors would like to extend their study across different centres to be able to recruit a larger number of individuals. 

At the BHD Foundation, we were excited by this approach and were encouraged that it has led to an increase in BHD diagnoses over the last 3 years. We look forward to seeing future studies in China and other East Asian countries to improve our understanding of BHD. We hope to establish a worldwide network to enable people with BHD to access the best possible care. 

On June 30th, we are celebrating World Pneumothorax Day. We will be raising awareness of the genetic causes of collapsed lungs. We would love for you to join us and help spread the word using our social media toolkit.  

The First Genetic Study of BHD in India

At the BHD Foundation, we support individuals with BHD worldwide. Much of the research on BHD has been done in Europe and the US and so we were excited to see the first study of BHD in India. The clinical and genetic features of 31 individuals with BHD from 15 families were studied. The individuals had been diagnosed based on their clinical symptoms rather than through genetic testing. 74 “asymptomatic” family members were also included in the study. These people did not have any BHD symptoms.

Clinical Features

  • 30 out of 31 individuals had lung symptoms (lung cysts and/or collapsed lungs).
  • 10 out of 31 individuals had fibrofolliculomas (skin bumps).
  • 3 out of 31 individuals had chromophobe kidney cancer.
  • The average age of onset of the first symptom was 44 years.

Reports from Western countries generally find the skin bumps to be the most common BHD symptom. However here, and in other studies from Eastern countries, they are reported less commonly. Instead, lung cysts and collapsed lungs are more frequent. The differences between the symptoms seen in these populations are currently unknown. It could be due to genetic differences or environmental factors. Another option is that the skin symptoms are simply less commonly reported or diagnosed. Increasing the number of reports like this one will help us address this question in the future.

Given the lung symptoms of BHD were the most common in this study, the authors looked more closely at these symptoms. 27 out of 31 individuals had experienced a pneumothorax (collapsed lung). 9 of these people had recurring pneumothoraces. The age of onset of a collapsed lung ranged from 15 to 59. The authors calculated the probability that an individual would have repeated collapsed lungs and found that the age at which the first collapsed lung occurred was an important factor. They found that people who had recurring pneumothoraces had their first collapsed lung at a younger age than those who only had a single collapsed lung.

Genetics

A mutation in folliculin (FLCN, the gene associated with BHD) was found in 19 of the 31 individuals from 10 of the 15 families.

11 of the 19 patients (from 5 families) had the same mutation: c.1285delC. This is the most common FLCN mutation and known to be a ‘hotspot’ for mutations in the FLCN gene. Our previous toolkit post helps you find out more about understanding genetic test results. All these individuals had lung cysts or collapsed lungs. The remaining families each had different mutations, of which 2 had not been previously reported.

A mutation in FLCN was also found in 16 of the 74 asymptomatic family members. The authors noted that the average age of these individuals was 29 and so they may still develop symptoms in the future.

A mutation in FLCN could not be found in 12 individuals from 5 families, even though they had BHD symptoms. There could be 2 possible explanations for this. The first is that there is a mutation in FLCN that could not be detected using the methods used in this study. The second is that there is no mutation in FLCN and perhaps another, unknown gene, is responsible for the symptoms seen in these individuals. Further work using a more sensitive type of sequencing would need to be performed to determine which explanation is correct. It would also be interesting to expand upon this work in the future to include more people with BHD. This would strengthen the current data and could help inform future diagnosis guidelines in different countries.

We are excited to see future reports from different countries reporting the clinical and genetic features of BHD. If you are an individual with BHD, or a clinician interested in BHD you can add yourself to our BHD Worldwide map.

Facebook Live Discussion with Pulse Infoframe

We recently held a Facebook Live to discuss our BHD Syndrome International Registry (BIRT). We discussed the benefits of signing up to BIRT and how you can help shape the future of BHD research. We were joined by our partners Pulse Infoframe who shared information on the privacy and security of their platform. We were also excited to be able to share some of the first results from the first 2 months of data collection.

Watch the recording of it below or download the transcript here.

Join the registry by signing up here.

How does Folliculin Regulate mTORC1 Activity?

Our cells need to be able to sense and respond to our body’s needs. Mechanistic target of rapamycin complex 1 (mTORC1) is a protein in our cells that acts as a central hub for this sensing ability. It can sense several inputs and can turn on or off different pathways (branches) in response to these stimuli. It is often described as a single on/off switch however this process is likely to be far more complicated than that. A recent paper by Li et al., has described specific regulation of different mTORC1 branches. 

Why is this relevant to Birt-Hogg-Dubé Syndrome (BHD)? BHD is caused by mutations in the gene folliculin (FLCN). The authors of the study found that FLCN was capable of specifically modifying mTORC1 function. It was able to turn on a specific branch of mTORC1 signalling without effecting the other pathways.

It has been shown previously that one of these mTORC1 branches is important for kidney tumour development in BHD. This pathway controls the activation of 2 related proteins called TFE3 and TFEB. These proteins are known as transcription factors. When they are turned on, they move from the cytoplasm to the nucleus (where DNA is located) and can trigger the expression of other proteins in our cells. Normally, when mTORC1 is active it modifies TFE3 and TFEB, so they stay in the cytoplasm (see the diagram below). This process is dependent on FLCN. So when cells are lacking FLCN, mTORC1 can no longer keep TFE3 and TFEB in the cytoplasm and they move to the nucleus. This results in expression of proteins that wouldn’t happen in cells containing FLCN and can drive tumour growth.  

The authors of this present study have built upon this knowledge to understand how FLCN is able to influence TFE3 signalling through mTORC1 without modifying other branches. They found that FLCN activates another protein called RagC. RagC physically recruits TFE3 to an area of the cell where it can be turned off by mTORC1. TFE3 is kept in the cytoplasm and unable to move to the nucleus. The researchers made a special form of RagC that was always on and didn’t need FLCN to activate it. They saw that this active form of RagC could turn off TFE3 signalling in cells that were lacking FLCN. This meant that this whole process is dependent on the activity of FLCN. This process could also happen without affecting any of the other functions of mTORC1. Additionally, when TFE3 is turned on it can drive the expression of other proteins that further activate mTORC1. This is known as a positive feedback loop and results in the hyperactivation of mTORC1.

Previous work has shown conflicting roles for mTORC1 in BHD. In some models with reduced FLCN, mTORC1 activation was shown to be reduced. However, in samples derived from BHD kidney tumours, hyperactivation of mTORC1 was observed. The mechanism proposed in this study has helped address this conflicting evidence. Activity of mTORC1 is often measured by looking at proteins that are turned on or off by mTORC1. The variations in these models could be explained by different researchers looking at proteins in different branches of mTORC1 signalling. For example, if one researcher looked at TFE3 activity they may have concluded that mTORC1 activation was reduced. However, if another group looked at a protein in another branch of mTORC1 signalling, they may have found hyperactivity of mTORC1.

This work is important because it helps us better understand how loss of FLCN can potentially lead to cancer development. Knowing which proteins FLCN interacts with, and the effect of that interaction can help guide the development of new anti-cancer treatments.

Being a doctor with BHD

Dr Bob was diagnosed with BHD after a routine scan accidentally picked up a mass on the top of his kidney. In this interview, we discuss how being a doctor affects his perspective of BHD, how we can raise awareness of BHD among doctors and the importance of being a patient advocate.

The transcript is available here.

Resources discussed in the interview.

Information resources for people with BHD

Information resources for researchers and doctors