title: Birt-Hogg-Dube syndrome is a novel ciliopathy.
abstract: 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.
authors.affiliation: Department of Dermatology and GROW School for Oncology and Developmental Biology.
authors.forename: Monique N H
authors.initials: MN
authors.lastname: Luijten
authors.forename: Sander G
authors.initials: SG
authors.lastname: Basten
authors.forename: Tijs
authors.initials: T
authors.lastname: Claessens
authors.forename: Marigje
authors.initials: M
authors.lastname: Vernooij
authors.forename: Claire L
authors.initials: CL
authors.lastname: Scott
authors.forename: Renske
authors.initials: R
authors.lastname: Janssen
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Easton
authors.forename: Miriam A F
authors.initials: MA
authors.lastname: Kamps
authors.forename: Maaike
authors.initials: M
authors.lastname: Vreeburg
authors.forename: Jos L V
authors.initials: JL
authors.lastname: Broers
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harbottle
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Nookala
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tee
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Land
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Coull
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
mesh_terms: D001483:Base Sequence; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D018385:Centrosome / Q000502:physiology; D002923:Cilia / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000502:physiology; D008870:Microtubules / Q000502:physiology; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins