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Positive diagnosis of any disease, common or rare, is essential an essential step and a logical precursor to successful treatment or clinical management. In the case of rare diseases like BHD Syndrome, recognising that you may have developed a symptom is made more difficult by lack of awareness of BHD Syndrome by both the general public and the medical community. By now regular readers of this blog and www.BHDsyndrome.org will know that BHD Syndrome predisposes to a triad of symptoms: fibrofolliculomas, pneumothorax and renal cancer.

However, a recent paper by Maffe et al, in Clinical Genetics presents the results of a clinical study of unrelated individuals presenting with the non-dermatological symptoms of BHD Syndrome, and amongst its conclusion the authors state that ‘parotid oncocytomas should be considered as a BHDS component manifestation, in addition to cutaneous, kidney, and pulmonary lesions’ because of its frequency amongst the cohort studied. Other symptoms associated with BHD Syndrome have been discussed in the literature and can be found summarised here. I think clinically, an awareness of all the relevant symptoms is essential for a timely diagnosis of BHD Syndrome.

www.BHDsyndrome.org is not a website that likes to rest on it’s laurels and to that effect it’s been regularly updated with new and original content since it’s creation, ensuring that it becomes the primary online reference site for anyone interested in BHD Syndrome.

However, we’d like to get your feedback on the scientific aspect of www.BHDsyndrome.org, to see what we’re doing right, and perhaps what we could be doing better!  If you have five minutes to spare, please head on over to our  survey by follwing the link below.

Researchers Feedback Survey – here

We’re also aware that non-scientists like to read this blog, and if you’d like to leave your feedback too, follow the link for the ‘Families’ section:

Families Feedback Survey – here

Last week I blogged about a newly published article in the journal Molecular Cancer (link). In it, the authors compared the growth (in vitro and in vivo) of a cell line containing a series of  wildtype or mutant FLCN transgenes; determining that wildtype FLCN suppressed xenograft tumour growth in vivo.

Gene expression profiling also showed that specific genes involved in angiogenesis, cadherin signalling and TGFβ signalling were differentially expressed in null or mutant FLCN expressing cell lines, compared to the wildtype. FLCN’s role in TGFβ signalling is the focus for the rest of the paper, rightfully so given the gravitas of TGFβ signalling in tumourigenesis. I also wonder whether the deregulation of angiogenesis and cadherin signalling are secondary adaptive measures that support tumourigenesis, or whether they occur downstream of the deregulation of TGFβ signalling in these tumours (or even both).

However, what I find particularly interesting is that when the authors examined how FLCN caused deregulation of TGFβ signalling, they showed that the phosphorylation status of downstream SMADs was unaffected by mutant FLCN, but that several downstream targets of TGFβ were, suggesting a role for FLCN in SMAD-independent TGFβ signalling. Whilst this finding is very exciting as it potentially places FLCN within a very specific signalling niche (potentially making it easier to examine), it may also prove to be a double edged sword since non-SMAD TGFβ signalling isn’t fully explored in itself, albeit because the SMADs themselves are so ubiquitous within the cell they’re a feature that can’t be ignored!

One of the biggest challenges currently facing BHD researchers is elucidating the role of FLCN’s within the cell. There’s no real way of fixing something unless you know how everything should normally fit into place, whether it be a bike, a car or even a human!

A new article in the journal Molecular Cancer, by Seung-Beom Hong et al¹ for me, is something to get quite excited about and I think that a lot of future research will look to this as it’s starting point.

Using an elegant combination of in vitro cell based assays, in vitro xenograft studies and gene expression profiles, the authors have successfully demonstrated that FLCN has an essential role in the regulation of components of TGF-β signalling and indeed confirm their deregulation in BHD-associated kidney tumours. This is a great step forward in understanding pathogenic mechanism underlying BHD syndrome and as such, throws up many new avenues for research that I’m sure will be followed up.

Regular readers will know that I usually dissect published information and try to look for synergy with other work in the area, and I’ll be doing so with all the data that this paper has generated in due course – I just thought I’d give everyone a heads up about its publication and why it’s so exciting.

1. Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS. Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer. 2010 Jun 23;9(1):160.

Two scientific stories in the press have caught my eye this week. The first was the announcement that the discovery of DNA, made by the now legendary scientists James Watson and Francis Crick in 1953, has been voted the UK’s greatest scientific breakthrough of all time. This single event has proved to be the birth of modern day genetics.

Flash forward to genetics in the current day (not discounting anything that has occurred between now and then) and the second story of interest concerns the sequencing of Ozzy Osbourne’s genome, in an attempt to gather insights into his longevity! Despite numerous addictions to alcohol, illegal narcotics and prescription drugs, the legendary front man of Black Sabbath and former party-animal, remains alive and healthy, much to the astonishment of the medical community. The sequencing is being carried out by Knome, a US based biotech company, with the aims of identifying any genetic variation that may have allowed him to ‘survive’ periods of great excess.

Whilst this story may seem topical, it highlights two significant matters: 1) that personalised genome sequencing, whilst currently expensive, is easily achievable and that; 2) current scientific thinking has established that an individual’s genetic variation may provide either a health advantage (or alternatively a predisposition to disease). This nicely bookends a blog I wrote two weeks ago, about how the potential effect of genetic variation within the FLCN gene should be accounted for, and takes it one step further: could there be some genetic modifiers that affect the expression of FLCN, and by extension, effect the phenotype of BHD Syndrome?

The development of renal cell carcinoma, fibrofolliculomas on the face and trunk and pneumothorax are the widely accepted ‘triad’ of symptoms associated with BHD Syndrome. It’s also important to consider that other clinical manifestations are associated (or at the very least, have been noted to co-occur) with BHD Syndrome in some cases. These include a range of benign and malignant tumours (detailed more fully by Menko et al, 2009*), but perhaps the association between colorectal cancer (CRC) and BHD syndrome is the most debated.

The earliest reports of BHD syndrome often described an association with CRC, but more recent genetic and clinical studies have provided conflicting data which only confuses matters further. A new article by Nahorski et al**, in the Journal of Medical Genetics, addresses this issue, and investigates the role of FLCN in sporadic CRC using combination of clinical and genetic methodologies. Their interesting results suggest that FLCN inactivation might contribute to colorectal tumourigenesis but you’ll have to read the paper yourself to find out the specifics (!). For me, this study represents an extremely informative investigation into an aspect of BHD Syndrome that’s ‘off the beaten trail’, since it doesn’t focus on the classic triad of symptoms previously mentioned, but is no less important, since identifying genotype-phenotype correlations could shed light on potential functional domains of the gene and in general adds to what we know about FLCN function.

Additionally, it’s important to keep in mind that the management and diagnosis of rarer diseases is often lead by current scientific findings (take the Menko* paper for example) and that providing medical professionals with a wider range of information about all the associated aspects of a disease is in the patient’s interest too.

*Menko FH et al, Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009 Dec; 10(12):1199-206

**Nahorski M et al, Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010 Jun; 47(6):385-90.

I attended the British Renal Society/Renal Association’s annual conference this week in Manchester, UK. It was well attended and addressed current clinical practice and basic research into a range renal disorders.  Unfortunately, there were no specific talks on BHD Syndrome but it was really interesting seeing how current renal genetics services were being integrated with established clinical pathways.

One specific talk on the subject of polycystic kidney disease highlighted the effect that certain genetic mutations can have on the phenotypic presentation of a disorder and I’d like to share that in the context of BHD.

We understand that BHD is a monogenic disorder, that is to say it’s caused by inactivation of a single gene, FLCN, which inevitably results in abnormal protein function within critical cell signalling pathways that underpin normal growth and development.

A range of causative pathogenic mutations have been identified (and even catalogued by Wei et al and Lim et al*). This has also lead to the development of a molecular diagnostic assay used to provide a positive diagnosis of BHD Syndrome.

It is essential to identify and characterise all mutations since some of these may act as pathogenic missense variants or hypomorphic alleles. Such mutations are not as immediately pathogenic as deleterious nonsense mutations but may be able to alter protein function if they arise within a highly conserved domain of the protein. They can account for milder phenotypes or even a disparity in the presentation of symptoms and significantly, rare missense variants can also be inherited and so give rise to familial disease.

*FLCN mutation databases by Wei et al: www.skingenedatabase.com; and Lim et al: www.lovd.nl/flcn

Amazingly, the BHD Research Blog has been going for nearly a year – my first post was way back in June 2009! It’s been an interesting period for me personally, expressing my opinion and thoughts on the ups and downs of BHD research and I hope to remain doing so for the foreseeable future. However what I can’t say is what’s going on in your lab right now and I think it’s something that would benefit all the scientists in the field…have you recently tried out a new FLCN antibody? Are you currently optimising a basic technique but having difficulties? This is what the BHD Resources forum was designed for. Go online and let people know if you’ve discovered something useful…by all means, don’t give away any confidential secrets, but a friendly ‘heads up’ could help out a BHD colleague!

A recent article published in the journal Chest by Young et al¹ investigated the efficacy of a serological diagnostic assay for VEGF-D in Lymphangioleiomyomatosis (LAM). LAM is a rare disease and is often cited as a subgroup of Tuberous Sclerosis Complex (TSC). It presents as cystic lung disease in women and is often fatal. Renal tumours (specifically angiolypomas) are also often found in LAM patients and so at phenotypically and not least because of its involvement in TSC, LAM resembles some aspects of BHD Syndrome (I should definitively note that the lung symptoms found in BHD has never proved fatal).

The authors were able to discriminate between individuals with sporadic-LAM and TSC associated-LAM and other patients presenting with cystic lung disease (including BHD) and healthy controls. Sporadic-LAM was significantly associated with serum VEGF-D levels of 800pg/ml and TSC associated LAM with serum VEGF-D levels of approximately 600pg/ml and ultimately suggest that use of serum VEGF-D as a prognostic assay for LAM is a viable technique, and by extension supports the use of VEGF-D as a clinical biomarker.

Unfortunately the individuals in the study with BHD were found to have serum VEGF-D levels comparable to the normal controls, so any hopes of increasing the sensitivity of the assay and applying it to BHD syndrome is unfounded. The study does imply that biochemically the lung symptoms of LAM and BHD differ in the context of VEGF-D involvement but importantly show that identifying biomarkers of disease (or even specific symptoms) is clinically relevant, especially in the case of BHD Syndrome where positive identification of a BHD associated pneumothorax could initiate renal surveillance before the development of renal tumours.

1. Young LR et al. Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis from Other Diseases. Chest. 2010 Apr 9 (Epublication ahead of print).