Birt-Hogg-Dube 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 A. M. van Steensel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

45 Citations (Web of Science)

Abstract

BirtHoggDub (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
JournalHuman Molecular Genetics
Volume22
Issue number21
DOIs
Publication statusPublished - 1 Nov 2013

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