BHD Research Blog

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263 posts · 154,450 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
263 posts

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  • October 18, 2013
  • 06:08 AM
  • 668 views

FLCN may act as a GAP towards RagC to induce mTOR signalling

by Joana Guedes in BHD Research Blog

It was recently reported that FLCN activates mTORC1 signalling in response to amino acid stimulation by interacting with RagA and RagB at the cytosolic lysosome surface, possibly by acting as a GEF towards these proteins (Petit et al., 2013). Another … Continue reading →... Read more »

  • October 11, 2013
  • 08:41 AM
  • 388 views

What is BHD?

by Joana Guedes in BHD Research Blog

Our BHD literature review, “What is BHD?”, in the “For Researchers” section of BHDSyndrome.org has been updated. This is the first major update since March 2011, and incorporates all literature published since then, including Tsun et al., 2013, who earlier … Continue reading →... Read more »

Gharbi H, Fabretti F, Bharill P, Rinschen MM, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU. (2013) Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner. Aging cell, 12(4), 593-603. PMID: 23566034  

Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S.... (2010) A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Human mutation, 31(1). PMID: 19802896  

Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, & Blundell TL. (2012) Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open biology, 2(8), 120071. PMID: 22977732  

Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G.... (2012) Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity, 36(5), 769-81. PMID: 22608497  

  • October 4, 2013
  • 06:49 AM
  • 493 views

FLCN and FNIP1 interact with Rags at the lysosome surface to activate mTORC1

by Joana Guedes in BHD Research Blog

mTOR signalling controls the balance of anabolic and catabolic cell metabolism, in response to the cellular environment. A link between FLCN and mTOR signalling was first reported in 2006 by Baba et al., and subsequent research has shown FLCN to … Continue reading →... Read more »

  • September 27, 2013
  • 05:04 AM
  • 880 views

FNIP1 is alternatively spliced during mesoderm differentiation

by Joana Guedes in BHD Research Blog

Earlier this year, it was reported that FLCN, along with its interacting partners FNIP1 and FNIP2, regulates stem cell exit from pluripotency. In stem cells, the pluripotency transcription factor TFE3 was found in the nucleus and able to activate target … Continue reading →... Read more »

Venables JP, Lapasset L, Gadea G, Fort P, Klinck R, Irimia M, Vignal E, Thibault P, Prinos P, Chabot B.... (2013) MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nature communications, 2480. PMID: 24048253  

  • September 20, 2013
  • 03:20 AM
  • 514 views

Autophagy dysregulation is a common feature of hereditary kidney cancer syndromes

by Joana Guedes in BHD Research Blog

Autophagy is an adaptive catabolic process which recycles cellular proteins and organelles to produce energy, allowing cells to survive in stressful conditions, such as hypoxia or starvation. Autophagy can promote cell survival or apoptosis, and as such both increased and … Continue reading →... Read more »

Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF. (2013) Folliculin Contributes to VHL Tumor Suppressing Activity in Renal Cancer through Regulation of Autophagy. PloS one, 8(7). PMID: 23922894  

Behrends C, Sowa ME, Gygi SP, & Harper JW. (2010) Network organization of the human autophagy system. Nature, 466(7302), 68-76. PMID: 20562859  

Gharbi H, Fabretti F, Bharill P, Rinschen MM, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU. (2013) Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner. Aging cell, 12(4), 593-603. PMID: 23566034  

Levine B, & Kroemer G. (2008) Autophagy in the pathogenesis of disease. Cell, 132(1), 27-42. PMID: 18191218  

Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ.... (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12455-60. PMID: 21746920  

Schiavi A, Torgovnick A, Kell A, Megalou E, Castelein N, Guccini I, Marzocchella L, Gelino S, Hansen M, Malisan F.... (2013) Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans. Experimental gerontology, 48(2), 191-201. PMID: 23247094  

Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL, & Wogan GN. (2013) Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proceedings of the National Academy of Sciences of the United States of America, 110(32). PMID: 23878245  

Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, & Giaccia AJ. (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer cell, 14(1), 90-102. PMID: 18598947  

  • September 13, 2013
  • 04:48 AM
  • 335 views

Is there a role for collagen in Birt-Hogg-Dubé syndrome?

by Joana Guedes in BHD Research Blog

Collagen is estimated to account for 25 – 35% of all protein in the human body (Canty and Kadler, 2005), responsible for maintaining the structure of fibrous tissues such as bone, tendons, ligaments and skin (DiLullo et al., 2002). However, … Continue reading →... Read more »

Scott RW, Hooper S, Crighton D, Li A, König I, Munro J, Trivier E, Wickman G, Morin P, Croft DR.... (2010) LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells. The Journal of cell biology, 191(1), 169-85. PMID: 20876278  

Scott RW, & Olson MF. (2007) LIM kinases: function, regulation and association with human disease. Journal of molecular medicine (Berlin, Germany), 85(6), 555-68. PMID: 17294230  

  • September 6, 2013
  • 05:07 AM
  • 594 views

A first step towards a gene therapy for BHD

by Joana Guedes in BHD Research Blog

The premise of gene therapy is to introduce a functional copy of a gene in to cells where one or both copies are missing, meaning that this approach is only appropriate for those diseases caused by a straightforward loss of gene … Continue reading →... Read more »

  • August 30, 2013
  • 04:32 AM
  • 565 views

Video interview: Dr Douglas Medvetz, Brigham and Women’s Hospital, USA

by Joana Guedes in BHD Research Blog

This week we would like to introduce you to the work of Dr Douglas Medvetz, a Post-Doctoral Research Fellow in Professor Elizabeth Henske’s team at Brigham and Women’s Hospital. Dr Medvetz moved to Professor Elizabeth Henske’s group in 2008, after … Continue reading →... Read more »

  • August 23, 2013
  • 04:00 AM
  • 356 views

Video interview: Professor Lisa Henske, Brigham and Women’s Hospital, USA

by Joana Guedes in BHD Research Blog

This week we would like to introduce you to the work of Professor Elizabeth Henske, Founding Director of the Centre for LAM Research and Clinical Care at Brigham and Women’s Hospital, Boston, MA. Dr Henske is also a Professor of … Continue reading →... Read more »

Carsillo T, Astrinidis A, & Henske EP. (2000) Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 6085-90. PMID: 10823953  

Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, & Henske EP. (2009) The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene, 28(13), 1594-604. PMID: 19234517  

Nahmias J, Hornigold N, Fitzgibbon J, Woodward K, Pilz A, Griffin D, Henske EP, Nakamura Y, Graw S, & Florian F. (1995) Cosmid contigs spanning 9q34 including the candidate region for TSC1. European journal of human genetics : EJHG, 3(2), 65-77. PMID: 7552144  

Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ.... (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12455-60. PMID: 21746920  

Yu JJ, Robb VA, Morrison TA, Ariazi EA, Karbowniczek M, Astrinidis A, Wang C, Hernandez-Cuebas L, Seeholzer LF, Nicolas E.... (2009) Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2635-40. PMID: 19202070  

  • August 16, 2013
  • 04:00 AM
  • 521 views

VHL tumour suppressor function is mediated by FLCN

by Joana Guedes in BHD Research Blog

Von Hippel-Lindau (VHL) syndrome is characterised by the development of tumours in multiple organ systems, including the kidney, and is caused by mutations in the VHL gene. As well as causing tumour development in the context of VHL syndrome, VHL … Continue reading →... Read more »

Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF. (2013) Folliculin Contributes to VHL Tumor Suppressing Activity in Renal Cancer through Regulation of Autophagy. PloS one, 8(7). PMID: 23922894  

  • August 9, 2013
  • 08:07 AM
  • 781 views

How do FLCN mutations cause BHD?

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé (BHD) syndrome is characterised by skin lesions; lung cysts and predisposition to pneumothoraces; and predisposition to kidney cancer. It is caused by inactivating mutations in the FLCN gene, and is inherited in an autosomal dominant manner. Although BHD is … Continue reading →... Read more »

Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA.... (2011) Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes, chromosomes , 50(6), 466-77. PMID: 21412933  

Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL.... (2013) Birt-Hogg-Dube syndrome is a novel ciliopathy. Human molecular genetics. PMID: 23784378  

Menko FH, Johannesma PC, van Moorselaar RJ, Reinhard R, van Waesberghe JH, Thunnissen E, Houweling AC, Leter EM, Waisfisz Q, van Doorn MB.... (2012) A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation. Familial cancer. PMID: 23264078  

Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X, Fenton J, Boora U, Nordenskjöld M, Latif F.... (2011) Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Human mutation, 32(8), 921-9. PMID: 21538689  

van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, Bladergroen RS, Steijlen PM, & van Geel M. (2007) Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. The Journal of investigative dermatology, 127(3), 588-93. PMID: 17124507  

Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, & Linehan WM. (2005) High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute, 97(12), 931-5. PMID: 15956655  

  • August 2, 2013
  • 03:00 AM
  • 450 views

Highlights from the 2013 Tuberous Sclerosis Alliance International Conference

by Joana Guedes in BHD Research Blog

In June of this year, the TS Alliance held its biennial international research conference in Washington, D.C. The conference was held over four days, bringing together scientists, clinicians and families to “examine the state of current knowledge, identify gaps, and … Continue reading →... Read more »

Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, & Manning BD. (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Molecular cell, 47(4), 535-46. PMID: 22795129  

Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM.... (2012) Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4(154). PMID: 23035046  

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM.... (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364(17), 1595-606. PMID: 21410393  

Yoshimura S, Egerer J, Fuchs E, Haas AK, & Barr FA. (2007) Functional dissection of Rab GTPases involved in primary cilium formation. The Journal of cell biology, 178(3), 363-9. PMID: 17646400  

  • July 26, 2013
  • 08:08 AM
  • 560 views

A case of adrenal carcinoma in a BHD patient

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé syndrome (BHD) is caused by mutations in the FLCN gene and characterised by fibrofolliculomas; lung cysts and increased predisposition to pneumothorax; and increased predisposition to kidney cancer. Other symptoms have been reported to be associated with BHD Syndrome, such … Continue reading →... Read more »

Raymond VM, Long JM, Everett JN, Caoili EM, Gruber SB, Stoffel EM, Giordano TJ, Hammer GD, & Else T. (2013) An Oncocytic Adrenal Tumor in a Patient with Birt-Hogg-Dubé Syndrome. Clinical endocrinology. PMID: 23848572  

  • July 19, 2013
  • 03:00 AM
  • 484 views

FLCN delays cell cycle progression

by Joana Guedes in BHD Research Blog

The cell cycle is tightly regulated and necessary for development, growth and tissue replacement and repair. The process requires both oncogenes, which drive the cell cycle forward, and tumour suppressor genes, which inhibit the cell cycle and can promote apoptosis … Continue reading →... Read more »

  • July 12, 2013
  • 03:00 AM
  • 306 views

Highlights from the 5th BHD and Second HLRCC symposium

by Joana Guedes in BHD Research Blog

Two weeks ago, more than 100 researchers, clinicians and patients attended the Fifth BHD and Second HLRCC Symposium in Paris, France. The conference was held over two days in the beautiful École du Louvre, which was founded in 1882 to … Continue reading →... Read more »

  • July 5, 2013
  • 10:09 AM
  • 841 views

Birt-Hogg-Dubé syndrome is a novel ciliopathy

by Joana Guedes in BHD Research Blog

Cilia are thin protuberances emanating from eukaryotic cells. Cilia fall in to two categories: primary and motile. Primary cilia are found on most cell types in the body, and are required for the cell to sense its environment. Motile cilia … Continue reading →... Read more »

Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL.... (2013) Birt-Hogg-Dube syndrome is a novel ciliopathy. Human molecular genetics. PMID: 23784378  

  • June 28, 2013
  • 12:00 PM
  • 346 views

DBHD, the Drosophila homologue of FLCN, regulates mTor signalling

by Joana Guedes in BHD Research Blog

While increasing evidence suggests that mammalian FLCN acts in a number of signalling pathways such as mTOR signalling, Rho signalling, membrane trafficking and stem cell exit from pluripotency, FLCN’s precise function, and how it causes the symptoms seen in BHD … Continue reading →... Read more »

  • June 21, 2013
  • 03:00 AM
  • 666 views

Rapamycin/Sirolimus – one drug, many uses

by Joana Guedes in BHD Research Blog

It is becoming increasingly clear that some rare diseases share characteristics in terms of both symptoms and underlying pathogenesis. Birt-Hogg-Dubé (BHD) syndrome is an excellent example of this.  BHD shares kidney symptoms with the cancer syndromes Von Hippel Lindau (VHL) … Continue reading →... Read more »

Canpolat M, Per H, Gumus H, Yikilmaz A, Unal E, Patiroglu T, Cinar L, Kurtsoy A, & Kumandas S. (2013) Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. PMID: 23743820  

Cappellano AM, Senerchia AA, Adolfo F, Paiva PM, Pinho R, Covic A, Cavalheiro S, & Saba N. (2013) Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. PMID: 23743818  

Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM.... (2012) Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4(154). PMID: 23035046  

Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, Wüthrich RP, & Serra AL. (2008) The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. The British journal of dermatology, 159(2), 473-5. PMID: 18547304  

Johnson SC, Rabinovitch PS, & Kaeberlein M. (2013) mTOR is a key modulator of ageing and age-related disease. Nature, 493(7432), 338-45. PMID: 23325216  

Laplante M, & Sabatini DM. (2012) mTOR signaling in growth control and disease. Cell, 149(2), 274-93. PMID: 22500797  

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM.... (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364(17), 1595-606. PMID: 21410393  

Mihaly Z, Sztupinszki Z, Surowiak P, & Gyorffy B. (2012) A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. Current cancer drug targets, 12(7), 857-72. PMID: 22515521  

Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X, Branca RM, Lehtiö J, Guan Z, Filipcik P.... (2013) Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis: IMPLICATION FOR ALZHEIMER DISEASE. The Journal of biological chemistry, 288(22), 15556-70. PMID: 23585566  

  • June 14, 2013
  • 03:00 AM
  • 503 views

Wellcome Trust Monitor – Public opinion about medical research

by Joana Guedes in BHD Research Blog

The Wellcome Trust Monitor documents the views of adults and young people in the UK about science and medical research.  The survey is conducted every three years, in order to capture how public opinion is changing over time and also … Continue reading →... Read more »

Genetic Alliance, & The New England Public Health Genetics Education Collaborative. (2010) Understanding Genetics:. A New England Guide for Patients and Health Professionals. PMID: 23586107  

Wilson SM. (2013) Professional development for science teachers. Science (New York, N.Y.), 340(6130), 310-3. PMID: 23599481  

  • June 7, 2013
  • 04:11 AM
  • 475 views

FLCN’s divergent DENN domain evolutionarily conserved

by Joana Guedes in BHD Research Blog

Last summer, Nookala et al., published the structure of the C-terminus of the FLCN protein, and showed that this portion of FLCN formed a divergent DENN domain. DENN domain proteins have Guanine nucleotide exchange factor (GEF) activity towards Rab GTPases, … Continue reading →... Read more »

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