The intellectual contribution made by the Baba paper (link), that folliculin, the protein encoded by the BHD gene, may interact with the 5’AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathway, a key regulator of cell growth and proliferation, paved the way for more informative studies.
A second Baba paper utilised a kidney-targeted BHD knockout mouse model to examine how loss of BHD affects kidney function, the potential pathways involved, and therapies that target those pathways (Baba et al, 2008). The group showed that BHD knockout mice died from renal failure and had enlarged cystic kidneys due to hyperproliferation and activation of the Erk1/2 and mTOR pathways. Treatment with the mTOR inhibitor drug rapamycin reduced kidney size and prolonged survival. This showed that loss of both copies of the BHD gene may lead to renal tumourigenesis in the mouse and indicated that this model may also be useful to determine the mechanisms of kidney carcinogenesis. Where you stand on the argument of using animal models is definitely an interesting argument, but will be one that I less than tactfully sidestep in this blog.
As an initial attempt to generate a BHD mouse model, this paper generates some excellent data. Not only is it the first animal BHD model but it’s also successful, yielding excellent results showing the effect of rapamycin and implicating the ERK signalling factor in the pathogenesis of BHD. Like all animal models, this mouse model will be useful in determining the additional genetic changes that may be required for progression to kidney carcinogenesis.