New Observations In Birt-Hogg-Dube Syndrome

A recent publication in PNAS (Hasumi Y. et al 2009. Homozygous loss of BHD causes early embryonic lethality and kidney tumour development with activation of mTORC1 and 2) raises a lot of very interesting issues.

The first important point is the generation of a BHD heterozygous knockout mouse model that develops a renal tumour phenotype that closely mimics the phenotype found in humans with BHD. Previous conditional BHD knockout mouse models have not displayed a phenotype that so closely resembles the clinical condition. This can only be a boon for scientific research in this area since tumourigenesis is a multistep process requiring the accumulation of genetic aberrations, having a model that develops hyperplastic kidney cysts, through to complex cysts and then progressing to solid tumours, not only provides further proof that this is indeed a multistep process, but provides an unparalleled tool with which to study this process.

The authors compared tumours from the mouse model with human BHD tumours and found activation of the PI3K-AKT-mTOR pathway in both, supporting a significant role for this pathway in the development of hyperplastic kidneys in BHD. Interestingly, the authors speculate that FLCN may post-translationally modify total levels of AKT in vivo since higher concentrations of total AKT were observed resulting in increased levels of phospho-AKT and activation of downstream effectors, something that has not been implied before.

Another important observation from this study is that BHD homozygous knockout mice were embryonic lethal and that this was caused by a loss of cell polarity in the developing embryo, resulting in a malformed proamniotic cavity. The authors suggest that normally, polarity in these tissues is controlled by LKB1 and AMPK and that in these null mice, inactivation of BHD leads to an alteration of LKB1/AMPK signalling resulting in embryonic lethality. This is another significant observation and adds to our understanding of the role of FLCN.

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