Up until several years ago a typical introduction to BHD Syndrome would go something like this:

“The gene responsible for BHD encodes for a protein called Folliculin which has no known function”

That’s right, no known function! This is a world away from more prevalent syndromes where genes have been identified, proteins have been characterised and functions elucidated. That’s what scientific research is about – trying to understand the process underlining a disease (for example) by breaking it down and seeing what’s really happening step by step.

Frustratingly with folliculin, the stairway just stops near the beginning. Luckily, we know a lot more now than we used to. If you’re a regular reader you’ll know that folliculin has been heavily implicated in the mTOR signalling pathway, and we know that several other genetic syndromes, similar to BHD, arise when other components of the mTOR pathway are compromised. This has shown that at the very lest, folliculin acts as a tumour suppressor gene and that when this function is compromised, individuals are predisposed to renal carcinoma and benign skin tumours. However, that doesn’t account for the third of the ‘BHD Triad’ – lung cysts and pneumothorax. This indicates that within the lung the tumour suppressing function of BHD is either not affected or somehow attenuated, or that there is another lung specific role that has been compromised. This is ofcourse not impossible, since proteins can have more than one function.

How can we solve this…? Most of the work elucidating the role of folliculin in renal cancer came off the back of a succesful mouse model. But generating successful animal models is not an easy thing to do. One option, and it seems obvious, is to use samples from BHD patients.

One newly published article has done just that. Koga et al (2009) carried out histopathological studies of dissected lung blebs from a BHD patient and found that they were distinctly different from ‘sporadic bullae’ or ‘blebs’.  This was also associated with a specific frameshift mutation within the folliculin gene that has previously been seen by Gunji et al (2007) in a case that showed familial pneumothorax but no fibrofolliculoma or renal cancer predisposition. It’s exciting to think that these studies are uncovering distinct genotype-phenotype associations but  there is no doubt that this needs to be followed up. Regardless, it’s a really good start at filling in the gaps about what we dont know about folliculin.