Birt-Hogg-Dubé syndrome is a novel ciliopathy

Cilia are thin protuberances emanating from eukaryotic cells. Cilia fall in to two categories: primary and motile. Primary cilia are found on most cell types in the body, and are required for the cell to sense its environment. Motile cilia tend to be present in higher numbers per cell and beat in a wave-like pattern in order to, for example, sweep airways clear of particles and mucus. Ciliopathies – diseases caused by ciliary defects – are characterised by the growth of cysts in multiple organs (Hildebrandt et al., 2011). A paper presented at the last week’s BHD & HLRCC Symposium by Professor Maurice van Steensel, suggests that BHD syndrome may also be a ciliopathy.

Luijten et al., show that FLCN localises to both primary and motile cilia in a number of different cell types. Interestingly, both knock down and overexpression of FLCN in HK-2 cells led to fewer cells with functional cilia at 72 hours. However, after 96 hours, the numbers of cells with cilia tended towards wild-type in both the FLCN-depleted and overexpressed experiments, suggesting that FLCN controls the onset of ciliogenesis, but is less important thereafter.

Similarly, the authors found that both reducing and increasing FLCN expression in IMCD3 cells reduced the number of cells with cilia, and concomitantly reduced lumen size in 3D spheroids. This suggests that, unlike wild-type cells, these cells do not divide in a controlled manner to generate a luminal space, but divide in multiple and incorrect orientations. FLCN has been previously shown to localise to the midbody during cytokinesis and to regulate RhoA signalling (Medvetz et al., 2012; Nahorski et al., 2012), which could account for the disordered cell division seen in these cultures. However, cilia present in the FLCN-null spheroids showed a reduction in β-catenin staining, while conversely, the amount of active phosphorylated β-catenin was increased in the cell body, as was expression of known β-catenin targets Axin2 and Cyclin D1. β-catenin is known to control planar cell polarity via the Wnt signalling pathway, and thus increased β-catenin activation could also account for the reduced lumen size in these spheroids.

FLCN has previously been shown to affect the expression of a number of Wnt signalling genes, to inhibit CyclinD1 expression, and the structure of FLCN suggests that it may function in membrane trafficking, a process which is vital for correct ciliary function (Hsiao et al., 2012). Additionally, FLCN has been shown to exclude TFE3 from the nucleus to promote the differentiation of stem cells, and has been hypothesised to sequester leucine into lysosomes, indicating it can control the localisation of other proteins.

Taken together, it is tempting to hypothesise that under normal conditions, FLCN initiates ciliogenesis and sequesters β-catenin in cilia through its membrane trafficking modality, hence reducing Wnt signalling in the cell body and allowing the cell to divide in the correct orientation, maintaining planar cell polarity. The fact that both reducing and increasing FLCN levels lead to the observed cilia defects suggests that the interaction between FLCN activity, Wnt signalling and planar cell polarity is a delicate balance, and that perturbation in either direction causes disordered cell division. Additionally, cilia defects in FLCN-null cells could also account for the uncoupling between nutrient sensing and mTOR signalling in these cells, as cilia are sensory organelles.

The data presented in this study, together with the observation that cystic lesions are a hallmark of ciliopathies, suggest that BHD is also a ciliopathy. The authors also note that renal cysts found in BHD patients have a similar histology to those found in the Nihon rat suggesting that, as in the Nihon rat, BHD-associated renal tumours may arise from renal cysts. Therefore further characterising FLCN’s role in cilia function and how this leads to cyst formation may identify a treatment to prevent tumour development.


  • Hildebrandt F, Benzing T, Katsanis N, 2011. Ciliopathies. The New England journal of medicine, 364 (16), 1533-43 PMID: 21506742
  • Hsiao YC, Tuz K, Ferland RJ, 2012. Trafficking in and to the primary cilium. Cilia, 1 (1), 4 PMID: 23351793
  • Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles R, Coull BJ, & van Steensel MA (2013). Birt-Hogg-Dube syndrome is a novel ciliopathy. Human molecular genetics PMID: 23784378
  • Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the Product of the Birt-Hogg-Dube Tumor Suppressor Gene, Interacts with the Adherens Junction Protein p0071 to Regulate Cell-Cell Adhesion. PloS one, 7 (11) PMID: 23139756
  • Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878

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