BHD Research Blog

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264 posts · 158,895 views

BHD Research Blog is the official blog of BHDSyndrome.org, the primary online resource for anyone interested in Birt-Hogg-Dubé Syndrome, a rare genetic condition linked to benign skin growths, collapsed lung and kidney cancers. In the BHD Research Blog, we focus on analysing current research in BHD and related fields, as well as considering wider issues relating to rare diseases.

Joana Guedes
264 posts

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  • May 19, 2017
  • 05:13 AM
  • 91 views

Characterization of a FLCN mutation associated with RCC

by Joana Guedes in BHD Research Blog

Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by renal cell carcinoma (RCC), pneumothorax and fibrofolliculomas. In their new study, Bartram et al. (2017) identify a heterozygous mutation in the FLCN gene in a patient with RCC. DNA from tumour and a metastasis was analysed and the authors demonstrated skipping of exon 11 as the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. The FLCN protein was still expressed but it was strongly destabilized and had a different subcellular localization. Both altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation.... Read more »

Bartram MP, Mishra T, Reintjes N, Fabretti F, Gharbi H, Adam AC, Göbel H, Franke M, Schermer B, Haneder S.... (2017) Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC medical genetics, 18(1), 53. PMID: 28499369  

  • April 20, 2017
  • 05:19 AM
  • 248 views

DHM attenuates obesity-induced slow-twitch-fiber decrease via FLCN/FNIP1/AMPK pathway

by Joana Guedes in BHD Research Blog

Obesity is often associated with decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Slow-twitch fibers are rich in mitochondria and utilize fatty acid oxidative phosphorylation for energy production. In their new study, Zhou et al. (2017) explore the role of the FLCN/FNIP1/AMPK signalling pathway in obesity-induced reductions in slow-twitch fibers and insulin sensitivity in skeletal muscle using high-fat-diet-induced (HFD) obese mice, ob/ob mutant mice, and palmitate-treated C2C12 myotubes. The authors also assess the effects of dihydromyricetin (DHM) on the obesity-induced decrease in slow-twitch fibers, and the molecular mechanisms responsible for this effect.... Read more »

  • April 7, 2017
  • 06:22 AM
  • 264 views

Novel FLCN mutations in Chinese patients

by Joana Guedes in BHD Research Blog

The gene FLCN is inactivated in individuals with BHD syndrome. The FLCN gene encodes the protein Folliculin, which is a putative tumour suppressor. Over 150 different FLCN mutations have been identified, most of which are likely to be pathogenic (LOVD-hosted FLCN mutation database). The majority of these mutations are frameshift, nonsense, insertion/deletion, or splice site mutations, resulting in truncation and inactivation of the encoded protein folliculin. FLCN consists of 14 exons spanning approximately 20 kb of genomic DNA (Nickerson et al., 2002).

Novel FLCN mutations are still being identified and here we discuss two case studies with novel mutations found in patients in China.... Read more »

  • March 24, 2017
  • 07:58 AM
  • 236 views

Ammonium regulates mTOR signalling

by Joana Guedes in BHD Research Blog

mTORC1 and mTORC2 are two distinct mammalian TOR (target of rapamycin) complexes that regulate cell growth and metabolism. In cancer, genetic alterations lead to activation of mTOR signalling impacting tumour metabolism. Upregulated glutaminolysis is part of the metabolic reaction occurring in cancer that liberates high levels of ammonium, a toxic waste product. Although the importance of glutamine as a tumour nutrient is recognized, little is known about the potential effects of ammonium produced by glutaminolysis in tumours. In their new study, Merhi et al., 2017 identify ammonium as a dose-dependent regulator of mTORC2, mTORC1 and of proliferation in cancer cells.... Read more »

  • March 10, 2017
  • 06:05 AM
  • 274 views

Spontaneous Pneumothorax and air travel in BHD Syndrome

by Joana Guedes in BHD Research Blog

Previous studies show that BHD syndrome causes spontaneous pneumothorax (SP) in 24-38% of patients, with a recurrence rate of up to 75% (Toro et al., 2007; Toro et al., 2008; Houweling et al., 2011). A common preventative strategy used following an initial SP in patients with BHD is pleurodesis, however, its efficacy in preventing recurrent episodes is not well known. Due to the pressure changes during air travel, cystic air spaces expand and compress in the thorax possibly leading to cyst rupture and pneumothorax. In their new study, Gupta et al. (2017) evaluate the risk of pneumothorax, the efficacy of pleurodesis, and the safety of air travel in patients with BHD.... Read more »

Gupta N, Kopras EJ, Henske EP, James LE, El-Chemaly S, Veeraraghavan S, Drake MG, & McCormack FX. (2017) Spontaneous Pneumothoraces in Patients with Birt-Hogg-Dubé Syndrome. Annals of the American Thoracic Society. PMID: 28248571  

  • March 3, 2017
  • 05:14 AM
  • 227 views

Rare Disease Day – Findacure Scientific Conference: Drug Repurposing for Rare Diseases

by Joana Guedes in BHD Research Blog

This year’s Findacure Scientific Conference took place in London on Rare Disease Day and was again focused on Drug Repurposing for Rare Diseases. The conference brought together over 100 representatives from patient groups, researchers and members of the healthcare industry to discuss the importance and the latest developments in drug repurposing for rare diseases.... Read more »

  • February 10, 2017
  • 07:19 AM
  • 329 views

BHD in patients undergoing chest CT and characteristics of BHD in Korea.

by Joana Guedes in BHD Research Blog

To date, there have been no prospective studies attempting to diagnose BHD syndrome or literature reviews on BHD in Korea. Park et al. (2017) address this in their new study that aims to detect BHD prospectively in patients undergoing chest computed tomography (CT) scans and to classify the characteristics of BHD in Korea.... Read more »

  • January 27, 2017
  • 05:13 AM
  • 563 views

TSC1 expression is affected by VHL alterations and HIF-1α production in clear-cell RCC

by Joana Guedes in BHD Research Blog

VHL genetic alterations do not affect the production of HIF-α in clear-cell renal cell carcinoma (ccRCC). However, their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expression are currently unknown. In a recent study, Damjanovic et al. (2016) evaluated the impact of VHL genetic alterations and HIF-α production on the expression of TSC proteins and Hsp90 in 47 sporadic ccRCCs and corresponding normal tissues.... Read more »

  • January 20, 2017
  • 05:19 AM
  • 392 views

RCC: Updates on Guidelines for Adjuvant Therapy and new drug combination

by Joana Guedes in BHD Research Blog

The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) guidelines panel has recently updated its recommendation on adjuvant therapy with sunitinib in non-metastatic RCC after surgical tumour removal (Bex et al., 2016). These clinical guidelines provide urologists with evidence-based information and recommendations for the management of RCC and the panel includes urological surgeons, oncologists, pathologists, radiologists and patient advocates. Based on the conflicting results of two available clinical studies (ASSURE and S-TRAC), the panel rated the quality of the evidence of the trials, the harm-to-benefit ratio, the patient preferences and the costs. As a result, the EAU panel, including representatives from a patient advocate group (International Kidney Cancer Coalition) voted and reached a consensus recommendation that adjuvant therapy with sunitinib for patients with high-risk RCC after nephrectomy should not be given.... Read more »

  • January 13, 2017
  • 05:11 AM
  • 381 views

Nutrient-dependent FNIP degradation regulates FLCN localization and promotes renal cancer progression

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé (BHD) syndrome is a rare disorder caused by mutations in FLCN and associated with increased risk of kidney cancer. It has been shown that FLCN-interacting protein 1 and 2 (FNIP1 and FNIP2) double knockout mice, like the FLCN knockout mice, develop renal carcinoma (Hasumi et al., 2015). However, the molecular mechanisms linking FNIP and FLCN remain unknown. In their new study, Nagashima et al. (2016) show that FNIP2 undergoes proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and association of mTOR, which promotes the proliferation of renal cancer cells.... Read more »

  • January 9, 2017
  • 04:48 AM
  • 359 views

H255Y and K508R missense mutations in FLCN promote kidney neoplasia

by Joana Guedes in BHD Research Blog

The germline FLCN missense mutations H255Y (Hasumi et al., 2009) and K508R (Toro et al., 2008) have been identified in patients with bilateral multifocal (BMF) kidney tumours and other clinical symptoms of Birt-Hogg-Dube (BHD) syndrome, or with BMF kidney tumours as the only manifestation. Building on their previous work identifying the H255Y mutation in human BHD kidney tumour, Hasumi et al. (2016) investigated whether these mutations have an impact on FLCN function. The authors evaluated the FLCN missense mutations, H255Y and K508R in genetically engineered mice, and demonstrated that they both are pathogenic mutations that promote aberrant kidney cell proliferation to different degrees, with the potential for malignancy. In addition, the phenotypic effect of the Flcn K508R mutant expression in mice with wild-type Flcn by expressing the Flcn K508R mutant transgene in heterozygous Flcn knockout mice was examined.... Read more »

  • December 30, 2016
  • 07:05 AM
  • 423 views

Annual review 2016

by Joana Guedes in BHD Research Blog

2016 has been a busy year for BHD research. With the new year approaching, this week’s blog will review the studies we’ve particularly enjoyed writing about and revisit the year’s highlights.... Read more »

Gupta, N., Sunwoo, B., & Kotloff, R. (2016) Birt-Hogg-Dubé Syndrome. Clinics in Chest Medicine, 37(3), 475-486. DOI: 10.1016/j.ccm.2016.04.010  

  • December 23, 2016
  • 06:43 AM
  • 464 views

Establishment of a new BHD Syndrome cell line

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé syndrome is caused by mutations in the FLCN gene. The FLCN protein acts as a tumour suppressor and BHD patients have a high risk of developing renal cell carcinoma (RCC). The mechanisms of tumour formation in BHD have been investigated using mouse models and human RCC tissues. However, in vitro signalling studies of human renal cells with mutant FLCN are still scarce. In a recent study, Furuya et al. (2016) established a new cell line from a BHD patient’s chromophobe RCC. The authors investigated FLCN mutations, chromosome profiles, and cytopathologic characteristics of the cell line to confirm its suitability for functional analysis of the typical phenotype of BHD-associated RCC with impaired FLCN.... Read more »

  • December 16, 2016
  • 05:25 AM
  • 452 views

Patient participation in clinical trials

by Joana Guedes in BHD Research Blog

Clinical trials are crucial to help doctors and scientists understand how to safely treat a particular condition, to evaluate new treatments and to test drug safety and efficacy. They have an important role in every step of managing a condition with different clinical trials helping with prevention, diagnosis, treatments and follow-up support.... Read more »

  • December 2, 2016
  • 07:48 AM
  • 447 views

Case studies: BHD syndrome associated with pulmonary malformation and with lung neoplasm

by Joana Guedes in BHD Research Blog

Matsutani et al. (2016) reported for the first time BHD syndrome accompanied by pulmonary arteriovenous malformation. The patient, a young male with no significant medical history, presented with chest pain. Chest X-ray and CT revealed emphysematous changes in both lungs and a tumour with pleural fluid. A thoracoscopy revealed dark red pleural fluid and multiple cysts in the lung. The tumour lesion was resected and identified as a non-malignant intrapulmonary hematoma caused by a significant haemorrhage in the pulmonary parenchyma, which was diagnosed as intrapulmonary hematoma. ... Read more »

Matsutani, N., Dejima, H., Takahashi, Y., Uehara, H., Iinuma, H., Tanaka, F., & Kawamura, M. (2016) Birt-Hogg-Dube syndrome accompanied by pulmonary arteriovenous malformation. Journal of Thoracic Disease, 8(10). DOI: 10.21037/jtd.2016.09.68  

Gunji-Niitsu, Y., Kumasaka, T., Kitamura, S., Hoshika, Y., Hayashi, T., Tokuda, H., Morita, R., Kobayashi, E., Mitani, K., Kikkawa, M.... (2016) Benign clear cell “sugar” tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report. BMC Medical Genetics, 17(1). DOI: 10.1186/s12881-016-0350-y  

  • November 25, 2016
  • 06:40 AM
  • 458 views

FLCN haploinsufficiency leads to lung fibroblast dysfunction in patients with BHD syndrome

by Joana Guedes in BHD Research Blog

Birt–Hogg–Dubé syndrome (BHD) is caused by germline mutations in the FLCN gene and characterized by fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal tumours. The stretch hypothesis for pulmonary cyst formation proposes that cysts in BHD arise from defects in cell–cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in vulnerable regions of lung (Kennedy et al., 2016). A new study by Hoshika et al. (2016) has shed some light on this mechanism. The authors isolated lung fibroblasts from BHD patients and evaluated them by testing chemotaxis to fibronectin and three-dimensional (3-D) gel contraction. They showed that FLCN is associated with chemotaxis in lung fibroblasts and that, together with reduced TGF-β1 expression by BHD lung fibroblasts, FLCN haploinsufficiency seems to cause lung fibroblast dysfunction, impairing tissue repair.... Read more »

Hoshika, Y., Takahashi, F., Togo, S., Hashimoto, M., Nara, T., Kobayashi, T., Nurwidya, F., Kataoka, H., Kurihara, M., Kobayashi, E.... (2016) Haploinsufficiency of the gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome . Physiological Reports, 4(21). DOI: 10.14814/phy2.13025  

  • November 18, 2016
  • 07:25 AM
  • 462 views

Mutated mTOR regulator RRAGC proteins decrease interactions with FLCN

by Joana Guedes in BHD Research Blog

Follicular lymphoma is a B-cell lymphoma that remains incurable with conventional therapies. Ying et al. (2016) present a new study exploring the biological and genetic features of follicular lymphoma and identifying potential new therapeutic targets. The authors identified recurrent mutations in the mTOR regulator RRAGC, a small G-protein, in approximately 10% of follicular lymphoma cases. Mutations in RRAGC localized to one protein surface area surrounding the GTP/GDP–binding sites. In stable retrovirally transfected HEK293T cells, multiple RRAGC mutations showed higher mTOR activation. A similar phenotype was observed in lymphoma cell lines and in yeast. Mutated RRAGC proteins showed increased binding to RPTOR, a binding protein for RRAG heterodimers, and decreased interactions with FLCN , a known tumour suppressor that plays a role in mTOR signalling and the causative gene of BHD syndrome.... Read more »

Ying ZX, Jin M, Peterson LF, Bernard D, Saiya-Cork K, Yildiz M, Wang S, Kaminski MS, Chang AE, Klionsky DJ.... (2016) Recurrent Mutations in the MTOR Regulator RRAGC in Follicular Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(21), 5383-5393. PMID: 27267853  

  • November 11, 2016
  • 05:10 AM
  • 449 views

RCC clinical trials: positive results and new phase III clinical study

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) is by far the most common type of kidney cancer and it can be caused by genetic conditions such as BHD (Randall et al., 2014). BHD patients can develop multiple kidney tumours. In most cases these tumours can be surgically removed. However, surgery and traditional chemotherapies can leave patients with reduced renal function and at risk of relapse. In addition, advanced or metastatic RCC is difficult to treat with surgery. Therefore, the development and improvement of molecular targeted drug treatments is becoming a very active field. The standard first-line treatment for RCC is an anti-angiogenic and anti-proliferative tyrosine kinase inhibitor (TKI) such as sunitinib or sorafenib. This blog summarises recent results from a clinical trial assessing a new RCC drug treatment and the initiation of a new study.... Read more »

  • November 4, 2016
  • 06:12 AM
  • 432 views

Two recent case reports on BHD – Epidemiologic study of patients in Asia and new FLCN mutation

by Joana Guedes in BHD Research Blog

Furuya et al. (2016) present a new study describing genetic, epidemiologic and clinicopathologic features of 312 Asian individuals with BHD manifestations based on data from 120 probands from different families (119 Japanese and 1 Taiwanese), 36 siblingss with genetic testing and 156 siblings without genetic testing.... Read more »

Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, Baba M, Matsushima J, Nomura F, & Nakatani Y. (2016) Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clinical genetics, 90(5), 403-412. PMID: 27220747  

  • October 28, 2016
  • 06:14 AM
  • 414 views

Lack of Tsc2 in Mesenchymal Cells Causes Kidney Cysts and Defective Lung Alveolarization

by Joana Guedes in BHD Research Blog

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that shares clinical similarities with BHD. TSC results from germline mutations in the Tsc1 or Tsc2 gene, affecting multiple organs, including the kidney and lung. In the kidney, lesions such as multiple renal cysts and renal cell carcinoma can occur. In the lung, patients can develop multifocal micronodular pneumocyte hyperplasia and LAM. TSC proteins are negative regulators of the mTORC1 pathway. The mechanisms of organ-specific manifestations in TSC remain unknown, and the impact of TSC on mesenchymal lineage cells has not yet been addressed. In a recent study, Ren et al. (2016) deleted Tsc2 specifically in mesoderm-derived mesenchymal cells in a variety of organs in mice. Inactivation of Tsc2 in mesoderm-derived cells caused impaired body growth, premature death, increased cell proliferation in the kidneys but reduced cell proliferation in the lungs, renal cysts, and deficient lung alveolarization.... Read more »

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