More research is required to understand the normal cellular function of FLCN. Understanding its normal function is crucial to understanding how FLCN mutation or loss can lead to the epidermal, pulmonary and renal phenotypes associated with BHD syndrome.
Most FLCN mutations lead to a frame shift and the introduction of a premature stop codon (Schmidt et al., 2005). However, it is unknown whether the resultant aberrant protein is degraded, or remains in the cell and exerts a dominant negative effect. In either case, the role of the C-terminus is unclear, but its loss suggests that this region is important in FLCN’s function. It is also unclear whether the remaining N-terminal region of FLCN can be re-purposed to fulfil the function of the wild-type protein.
Additionally, localisation experiments have observed FLCN in the cell nucleus and the cytoplasm (Takagi et al., 2008). How, where, when and why FLCN is localised to different subcellular compartments, is still unknown.
Research identified a role for FLCN in the mTOR signalling pathway (Baba et al., 2006; Baba et al., 2008; Hartman et al., 2009; Piao et al., 2009; Hasumi et al., 2009; Hudon et al., 2010). This role has recently been extended into several other processes: JAK-STAT signalling (Singh et al., 2006); MAPK/ERK signalling (Baba et al., 2008); TGF-β signalling (Hong et al., 2010a; Cash et al., 2011); HIF signalling (Preston et al., 2010); mitochondrial biogenesis (Klomp et al., 2010); and general transcriptional regulation (Hong et al., 2010b). Understanding the role of FLCN in these, and additional, processes will provide insight into the mechanism of pathogenesis of BHD syndrome.
The two proteins known to bind FLCN – FNIP1 and FNIP2 – are themselves poorly characterised. It is possible that additional proteins bind to FLCN, which remain to be identified. The function of the FLCN-FNIP1 and -FNIP2 complexes are also an area of future work. Characterising FLCN’s interactions with other proteins, and the functions of FLCN-containing protein complexes, will provide insight into how FLCN mutation or loss affects cellular function. These interacting proteins may modulate the phenotype of BHD syndrome and thus affect its variability.
Happloinsufficiency is thought to be sufficient for the skin and lung phenotype, but loss of heterozygosity is required for the development of renal carcinomas. Characterising not only the process by which the second FLCN allele is lost, but also the differences in gene transcription and protein expression profiles in cells with two, one or no copies of wild-type FLCN, may provide insight into BHD’s phenotype variability.
