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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  • February 3, 2012
  • 10:17 AM
  • 1,154 views

Gene therapy in VHL-null cells using human artificial chromosomes

by Joana Guedes in BHD Research Blog

Last month, our conference summary highlighted some of the work that is taking place in the field of gene therapy. Currently, many advanced gene therapy systems are derived from viruses, such as the adenovirus and lentivirus. However, these viral vectors … Continue reading →... Read more »

Kim JH, Kononenko A, Erliandri I, Kim TA, Nakano M, Iida Y, Barrett JC, Oshimura M, Masumoto H, Earnshaw WC.... (2011) Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells. Proceedings of the National Academy of Sciences of the United States of America, 108(50), 20048-53. PMID: 22123967  

  • January 27, 2012
  • 04:45 AM
  • 566 views

Video Interview: Dr Tim Cash – Abramson Family Cancer Research Institute

by Joana Guedes in BHD Research Blog

This week we highlight the work of Dr Tim Cash, who worked on BHD syndrome as part of his PhD studies in the lab of Professor Celeste Simon at the Abramson Family Cancer Research Institute, University of Pennsylvania. Dr Cash … Continue reading →... Read more »

  • January 20, 2012
  • 05:31 AM
  • 531 views

FLCN-FNIP2-AMPK and MNU-induced apoptosis

by Joana Guedes in BHD Research Blog

DNA repair proteins appear to play a significant role in both the development and progression of renal cell carcinoma, as has been discussed in earlier blog posts from 2010 and 2011. These proteins are responsible for repairing DNA lesions caused … Continue reading →... Read more »

  • December 30, 2011
  • 06:33 AM
  • 555 views

The ubiquitin-mediated proteolysis pathway and clear cell RCC

by Joana Guedes in BHD Research Blog

Mutations in VHL are known to be associated with the development of clear cell renal cell carcinoma (ccRCC), and recent sequencing studies have identified several genes involved in chromatin regulation that are also frequently mutated in ccRCC (Dalgliesh et al., 2010; … Continue reading →... Read more »

Dalgliesh, G., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C.... (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463(7279), 360-363. DOI: 10.1038/nature08672  

Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J.... (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature, 469(7331), 539-42. PMID: 21248752  

  • December 22, 2011
  • 04:20 AM
  • 478 views

Video Interview: Dr Seung-Beom Hong – University of Pennsylvania, USA

by Joana Guedes in BHD Research Blog

This week we would like to introduce Dr Seung-Beom Hong, a post-doctoral researcher in the lab of Professor Vera Krymskaya at the University of Pennsylvania. Dr Hong was part of the group at the NIH that helped to identify and … Continue reading →... Read more »

Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP.... (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings of the National Academy of Sciences of the United States of America, 106(44), 18722-7. PMID: 19850877  

Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, & Schmidt LS. (2008) Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene, 415(1-2), 60-7. PMID: 18403135  

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

Hong SB, Furihata M, Baba M, Zbar B, & Schmidt LS. (2006) Vascular defects and liver damage by the acute inactivation of the VHL gene during mouse embryogenesis. Laboratory investigation; a journal of technical methods and pathology, 86(7), 664-75. PMID: 16652107  

  • December 16, 2011
  • 04:29 AM
  • 4,200 views

Estimating the risk of pneumothorax and renal cell carcinoma in BHD patients

by Joana Guedes in BHD Research Blog

Many studies into BHD syndrome have investigated the prevalence of pneumothorax and renal cell carcinoma amongst FLCN mutation carriers. Previous estimations of the RCC risk have varied from 6.5% to 34% (Toro et al., 2008), and for pneumothorax, from 24% … Continue reading →... Read more »

Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J.... (2005) Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics, 76(6), 1023-33. PMID: 15852235  

Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B.... (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175(10), 1044-53. PMID: 17322109  

Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH.... (2011) Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British journal of cancer, 105(12), 1912-9. PMID: 22146830  

Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, & Merino MJ. (2002) Renal tumors in the Birt-Hogg-Dubé syndrome. The American journal of surgical pathology, 26(12), 1542-52. PMID: 12459621  

Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER.... (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. The lancet oncology, 10(12), 1199-206. PMID: 19959076  

  • December 2, 2011
  • 05:59 AM
  • 604 views

A HIF-independent pathway for tumourigenesis in HLRCC

by Joana Guedes in BHD Research Blog

HLRCC, caused by mutations in FH, predisposes patients to develop papillary renal cell carcinoma. FH-deficient cells have an accumulation of fumarate, which leads to the stabilisation of HIF-α subunits and therefore an increase in HIF-α levels. An increased expression of … Continue reading →... Read more »

Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ.... (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell, 20(4), 511-23. PMID: 22014576  

Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A.... (2011) Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477(7363), 225-8. PMID: 21849978  

  • November 25, 2011
  • 04:41 AM
  • 648 views

TSC clinical trials

by Joana Guedes in BHD Research Blog

In our last conference summary, it was noted that a number of clinical trials are underway to find an effective treatment for tuberous sclerosis complex (TSC). These trials use the mTORC1 inhibitors rapamycin and everolimus to compensate for mutations in … Continue reading →... Read more »

Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J.... (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. The New England journal of medicine, 358(2), 140-51. PMID: 18184959  

Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K.... (2011) Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clinical cancer research : an official journal of the American Association for Cancer Research, 17(12), 4071-81. PMID: 21525172  

Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, & Franz DN. (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. The New England journal of medicine, 363(19), 1801-11. PMID: 21047224  

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  

  • November 18, 2011
  • 04:00 AM
  • 545 views

Degradation of HIF-1α by Hypericin

by Joana Guedes in BHD Research Blog

Hypoxia inducible factor (HIF) regulates processes such as cell proliferation and metabolism, and it has been implicated in tumour growth in several disorders such as VHL and TSC. Preston et al. (2010) demonstrated that HIF-1α activity was increased in FLCN-null … Continue reading →... Read more »

Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, & Neckers LM. (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. The Journal of biological chemistry, 277(33), 29936-44. PMID: 12052835  

  • November 4, 2011
  • 05:12 AM
  • 850 views

Lab-profile: prof. dr. Maurice van Steensel – University Hospital Maastricht

by Joana Guedes in BHD Research Blog

In this month’s lab-profile we introduce Professor Maurice van Steensel, a Professor of genetic dermatology at the University Hospital Maastricht. Professor van Steensel leads a research group studying the role of FLCN in BHD syndrome and he is also a … Continue reading →... Read more »

Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, & van Steensel MA. (2010) Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome. Nature reviews. Urology, 7(10), 583-7. PMID: 20842188  

Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER.... (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. The lancet oncology, 10(12), 1199-206. PMID: 19959076  

  • October 28, 2011
  • 05:44 AM
  • 652 views

Conference reports

by Joana Guedes in BHD Research Blog

In July, the Beatson International Cancer Conference took place at The Beatson Institute for Cancer Research in Glasgow, UK. The Beatson Institute is a Cancer Research UK-funded centre which focuses on understanding cancer cell behaviour and developing new therapies and … Continue reading →... Read more »

  • October 21, 2011
  • 05:27 AM
  • 597 views

HDAC4… not only a histone deacetylase

by Joana Guedes in BHD Research Blog

HIF1α is a transcriptional regulator which plays an essential role in the cellular response to hypoxia. As discussed in last week’s blog, prolyl hydroxylases (PHDs) mark HIFα subunits for degradation, but HIF1α can also be regulated by reversible acetylation. Earlier … Continue reading →... Read more »

Geng H, Harvey CT, Pittsenbarger J, Liu Q, Beer TM, Xue C, & Qian DZ. (2011) HDAC4 regulates HIF1{alpha} lysine acetylation and cancer cell response to hypoxia. The Journal of biological chemistry. PMID: 21917920  

  • October 14, 2011
  • 04:00 AM
  • 627 views

Reduced AMPK and cytosolic iron levels in FH-deficient cells

by Joana Guedes in BHD Research Blog

Mutations in Fumarate Hydratase (FH) cause HLRCC, a kidney cancer syndrome related to BHD. FH is an enzyme involved in the TCA cycle and its deficiency results in the accumulation of fumarate within the cell. This accumulation leads to increased … Continue reading →... Read more »

  • October 7, 2011
  • 04:38 AM
  • 612 views

Video Interview: Dr Derek Lim – University of Birmingham, UK

by Joana Guedes in BHD Research Blog

As mentioned in our latest newsletter, several new interviews were filmed at the Third BHD Symposium, and have been posted to BHDSyndrome.org. Dr Derek Lim’s work at the University of Birmingham has been described previously, including his contribution to the … Continue reading →... Read more »

Lim, D., Rehal, P., Nahorski, M., Macdonald, F., Claessens, T., Van Geel, M., Gijezen, L., Gille, J., Giraud, S., Richard, S.... (2010) A new locus-specific database (LSDB) for mutations in the folliculin ( ) gene . Human Mutation, 31(1). DOI: 10.1002/humu.21130  

  • September 23, 2011
  • 04:28 AM
  • 607 views

A case report of localised fibrofolliculomas

by Joana Guedes in BHD Research Blog

In order to further understand the clinical aspects and symptoms of BHD syndrome, it is important that novel findings discovered during patient analysis are published in case reports. This assists in unravelling genotype-phenotype correlations, and also in identifying trends, for … Continue reading →... Read more »

Alonso-González J, Rodríguez-Pazos L, Fernández-Redondo V, Vega-Gliemmo A, & Toribio J. (2011) Birt-Hogg-Dubé syndrome in a patient with localized fibrofolliculomas and a novel mutation in the FLCN gene. International journal of dermatology, 50(8), 968-71. PMID: 21781069  

Kluger N, Giraud S, Coupier I, Avril MF, Dereure O, Guillot B, Richard S, & Bessis D. (2010) Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. The British journal of dermatology, 162(3), 527-37. PMID: 19785621  

Schulz T, Ebschner U, & Hartschuh W. (2001) Localized Birt-Hogg-Dubé syndrome with prominent perivascular fibromas. The American Journal of dermatopathology, 23(2), 149-53. PMID: 11285413  

Starink TM, Houweling AC, van Doorn MB, Leter EM, Jaspars EH, van Moorselaar RJ, Postmus PE, Johannesma PC, van Waesberghe JH, Ploeger MH.... (2011) Familial multiple discoid fibromas: A look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus. Journal of the American Academy of Dermatology. PMID: 21794948  

  • September 16, 2011
  • 10:03 AM
  • 1,165 views

Tuberous sclerosis complex and autophagy

by Joana Guedes in BHD Research Blog

Tuberous sclerosis complex (TSC) is a multi-system disorder caused by mutations in the TSC1 or TSC2 genes. As illustrated in the signalling diagram on BHDSyndrome.org, TSC1/2 plays an important role in regulating the mammalian target of rapamycin complex 1 (mTORC1), which is involved … Continue reading →... Read more »

Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C.... (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell, 137(6), 1062-75. PMID: 19524509  

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  

  • September 9, 2011
  • 04:00 AM
  • 1,057 views

Lab-profile: Dr Ravi Nookala – University of Cambridge, UK

by Joana Guedes in BHD Research Blog

In this month’s lab profile we highlight the work of Dr Ravi Nookala, a structural biologist working in the lab of Professor Sir Tom Blundell in the Department of Biochemistry at the University of Cambridge. Dr Nookala is working on … Continue reading →... Read more »

Nookala RK, Hussain S, & Pellegrini L. (2007) Insights into Fanconi Anaemia from the structure of human FANCE. Nucleic acids research, 35(5), 1638-48. PMID: 17308347  

  • September 2, 2011
  • 04:27 AM
  • 1,075 views

Synthetic lethality as a treatment for HLRCC

by Joana Guedes in BHD Research Blog

In the blog last week, I introduced synthetic lethality as a potential strategy for cancer therapy which targets tumour cells whilst having no effect on healthy tissue. Another synthetic lethality paper has recently been published in Nature, this time targeting … Continue reading →... Read more »

Frezza C, Zheng L, Folger O, Rajagopalan KN, Mackenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A.... (2011) Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. PMID: 21849978  

  • August 26, 2011
  • 04:00 AM
  • 1,161 views

Selectively targeting renal cell carcinoma by synthetic lethality

by Joana Guedes in BHD Research Blog

A major challenge in developing effective cancer therapies is targeting the tumour cells without harming the surrounding healthy tissue. A technique often used to identify such drugs is synthetic lethality. The basis of this technique is that the inhibition of … Continue reading →... Read more »

  • August 19, 2011
  • 04:23 AM
  • 1,375 views

Familial multiple discoid fibromas

by Joana Guedes in BHD Research Blog

In 1985, Starink et al. described patients with hereditary multiple trichodiscomas, a skin condition which was proposed to be distinct from Birt-Hogg-Dubé syndrome. However, trichodiscomas are firm, skin-coloured flat or dome-shaped papules, and their similarity to fibrofolliculomas has meant that … Continue reading →... Read more »

Starink TM, Houweling AC, van Doorn MB, Leter EM, Jaspars EH, van Moorselaar RJ, Postmus PE, Johannesma PC, van Waesberghe JH, Ploeger MH.... (2011) Familial multiple discoid fibromas: A look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus. Journal of the American Academy of Dermatology. PMID: 21794948  

Starink TM, Kisch LS, & Meijer CJ. (1985) Familial multiple trichodiscomas. A clinicopathologic study. Archives of dermatology, 121(7), 888-91. PMID: 4015134  

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