Birt-Hogg-Dubé syndrome is a novel ciliopathy

Monique N.H. Luijten, Sander G. Basten, Tijs Claessens, Marigje Vernooij, Claire L. Scott, Renske Janssen, Jennifer A. Easton, Miriam A.F. Kamps, Maaike Vreeburg, Jos L.V. Broers, Michel van Geel, Fred H. Menko, Richard P. Harbottle, Ravi K. Nookala, Andrew R. Tee, Stephen C. Land, Rachel H. Giles, Barry J. Coull, Maurice van Steensel

    Research output: Contribution to journalArticlepeer-review

    63 Citations (Scopus)


    Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder where patients are predisposed to kidney cancer, lung and kidney cysts and benign skin tumors. BHD is caused by heterozygous mutations affecting folliculin (FLCN), a conserved protein that is considered a tumor suppressor. Previous research has uncovered multiple roles for FLCN in cellular physiology, yet it remains unclear how these translate to BHD lesions. Since BHD manifests hallmark characteristics of ciliopathies, we speculated that FLCN might also have a ciliary role. Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. Alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. In three-dimensional culture, abnormal expression of FLCN disrupts polarized growth of kidney cells and deregulates canonical Wnt signalling. Our findings further suggest that BHD-causing FLCN mutants may retain partial functionality. Thus, several BHD symptoms may be due to abnormal levels of FLCN rather than its complete loss and accordingly, we show expression of mutant FLCN in a BHD-associated renal carcinoma. We propose that BHD is a novel ciliopathy, its symptoms at least partly due to abnormal ciliogenesis and canonical Wnt signalling.
    Original languageEnglish
    Pages (from-to)4383-4397
    Number of pages15
    JournalHuman Molecular Genetics
    Issue number21
    Early online date6 Jul 2013
    Publication statusPublished - 2013


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