Our goal in life is experimental molecular dermatology. We focus on the molecular genetics and biology of rare genetic skin disorders, but we also study the impact of epigenetic changes on common diseases, including the most frequent human malignancy: basal cell carcinoma.
We apply the tools and knowledge obtained from the rare to the study of the common. Our mission is to understand skin disease at its most basic level so that we can offer our patients rational and effective treatments for their conditions.
Result of the month
Human Molecular Genetics advance access:
Birt-Hogg-Dubé syndrome is a novel ciliopathy
- Monique N. H. Luijten1,+, Sander G. Basten2,3,+, Tijs Claessens1,5,+, Marigje Vernooij1,Claire L. Scott4, Renske Janssen1, Jennifer A. Easton1, Miriam A. F. Kamps1,Maaike Vreeburg6, Jos L. V. Broers7, Michel van Geel1, Fred H. Menko8,Richard P. Harbottle9, Ravi K. Nookala10, Andrew R. Tee5, Stephen C. Land4, Rachel Giles2,Barry J. Coull1,* and Maurice A. M. van Steensel1,6
- 1Department of Dermatology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
- 2Department of Nephrology and Hypertension University Medical Centre Utrecht, Heidelberglaan 100 F03.233, 3584CXUtrecht, The Netherlands
- 3Department of Medical Oncology,University Medical Centre Utrecht, Heidelberglaan 100 F02.126 3584CXUtrecht, The Netherlands
- 4Division of Cardiovascular and Diabetes Medicine,Medical Research InstituteNinewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SYScotland, UK
- 5Institute of Medical Genetics Cancer Genetics Building Cardiff UniversityHeath Park WayCardiffCF14 4XN UK
- 6Department of Molecular Cell Biology GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
- 7Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands
- 8Department of Clinical Genetics VU Medical Centre Amsterdam, The Netherlands
- 9Gene Therapy Research Group Molecular Medicine Imperial College London Sir Alexander Fleming Building Imperial College Road South Kensington London SW7 2AZ UK
- 10Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
- ↵+ Equal contribution
Received April 19, 2013.
Revision received June 11, 2013.
Accepted June 14, 2013.
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder where patients are predisposed to kidney cancer, lung and kidney cysts, and benign skin tumours. BHD is caused by heterozygous mutations affecting folliculin (FLCN), a conserved protein that is considered a tumour 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 indicates that FLCN localises 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 polarised 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.
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