Birt-Hogg-Dube syndrome is a novel ciliopathy

TY - JOUR

T1 - Birt-Hogg-Dube syndrome is a novel ciliopathy

AU - Luijten, Monique N H

AU - Basten, Sander G

AU - Claessens, Tijs

AU - Vernooij, Marigje

AU - Scott, Claire L

AU - Janssen, Renske

AU - Easton, Jennifer A

AU - Kamps, Miriam A F

AU - Vreeburg, Maaike

AU - Broers, Jos L V

AU - van Geel, Michel

AU - Menko, Fred H

AU - Harbottle, Richard P

AU - Nookala, Ravi K

AU - Tee, Andrew R

AU - Land, Stephen C

AU - Giles, Rachel H

AU - Coull, Barry J

AU - van Steensel, Maurice A M

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

KW - Base Sequence

KW - Birt-Hogg-Dube Syndrome

KW - Cell Line

KW - Cell Polarity

KW - Cell Proliferation

KW - Centrosome

KW - Cilia

KW - Humans

KW - Kidney

KW - Microtubules

KW - Molecular Sequence Data

KW - Proto-Oncogene Proteins

KW - Sequence Analysis, DNA

KW - Tumor Suppressor Proteins

KW - Wnt Signaling Pathway

U2 - 10.1093/hmg/ddt288

DO - 10.1093/hmg/ddt288

M3 - Article

C2 - 23784378

SN - 0964-6906

VL - 22

SP - 4383

EP - 4397

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 21

ER -