Guest blog written by Neil Pearson
Birt-Hogg-Dubé syndrome (also known as BHD) is a dominant hereditary condition that causes skin lesions, lung cysts, collapsed lungs, and kidney cancer. BHD mainly affects adults, with symptoms usually appearing in a person’s 20s and 30s. BHD is caused by variants (mutations) in the Folliculin (FLCN) gene that result in a loss of function leading to the observed symptoms.
Researchers in Denmark focused on rare BHD-linked FLCN mis-sense variants and found they caused misfolding and degradation of the FLCN protein. Mis-sense variants often result in misfolded proteins which can be toxic and need to be removed from the cell via the protein quality control (PQC) network. Because this system takes a “better safe than sorry” approach it often removes misfolded proteins that would otherwise be functional. This has been observed in some mis-sense variants of the Cystic Fibrosis, CFTR gene. It may also be the case that some BHD-linked variants would be functional if they were not degraded by the PQC network. Drugs that stabilise the misfolded FLCN protein or block its degradation could be a potential therapeutic target for some types of BHD.
The research also used computer modelling to predict variants that result in misfolding and degradation by the PQC. Further research into whether these predicted variants are actually degraded in cells will strengthen these predictions. This could help diagnose BHD when variants of uncertain clinical significance are found in patients.
References
Interesting! The paper points out there are two major pathways for clearance of unstable proteins, and the autophagy route seems not to be used for these FLCN variants. Could this be because autophagy is impaired with certain FLCN variants? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198360/
The fact that most of these missense and in-frame deletion variants are degraded quickly explains why for these (as for nonsense mutations) it is rare to find a correlation between altered structure and altered function. Function seems to be either off or on, as far as I’m aware. As the authors point out, the the less-destabilized V400I and K508R variants may be exceptions to this: it is more likely that any potential pathogenicity associated with these variants is “not caused by structural destabilization, but instead associated with other properties of the FLCN protein that were not tested here.”