Birt-Hogg-Dube syndrome is a novel ciliopathy

被引：56

作者：

Luijten, Monique N. H. ^{[1
,2
]}

Basten, Sander G. ^{[5
,6
]}

Claessens, Tijs ^{[1
,2
,8
]}

Vernooij, Marigje ^{[1
,2
]}

Scott, Claire L. ^{[7
]}

Janssen, Renske ^{[1
,2
]}

Easton, Jennifer A. ^{[1
,2
]}

Kamps, Miriam A. F. ^{[1
,2
]}

Vreeburg, Maaike ^{[4
]}

Broers, Jos L. V. ^{[3
]}

van Geel, Michel ^{[1
,2
,4
]}

Menko, Fred H. ^{[9
]}

Harbottle, Richard P. ^{[10
]}

Nookala, Ravi K. ^{[11
]}

Tee, Andrew R. ^{[8
]}

Land, Stephen C. ^{[7
]}

Giles, Rachel H. ^{[5
]}

Coull, Barry J. ^{[1
,2
]}

van Steensel, Maurice A. M. ^{[1
,2
,4
]}

机构：

[1] Maastricht Univ, Med Ctr, Dept Dermatol, Maastricht, Netherlands

[2] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands

[3] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Mol Cell Biol, Maastricht, Netherlands

[4] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands

[5] Univ Med Ctr Utrecht, Dept Hypertens & Nephrol, NL-3584 CX Utrecht, Netherlands

[6] Univ Med Ctr Utrecht, Dept Med Oncol, NL-3584 CX Utrecht, Netherlands

[7] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee DD1 9SY, Scotland

[8] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales

[9] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[10] German Canc Res Ctr, Gene Therapy Res Grp, D-69120 Heidelberg, Germany

[11] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 21期

基金：

英国惠康基金;

关键词：

PLANAR CELL POLARITY; MTOR ACTIVATION; PRIMARY CILIUM; GENE-PRODUCT; RENAL-CANCER; PROTEIN; KIDNEY; FOLLICULIN; MUTATIONS; MODEL;

D O I：

10.1093/hmg/ddt288

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4383 / 4397

页数：15

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