Copyright Myrovlytis Trust October, 2013 What is BHD? Contents 1. Introduction – Birt–Hogg–Dubé syndrome ......................................................................................... 3 1.1 BHD Families ....................................................................................................................... 4 2. Clinical manifestations of BHD syndrome ........................................................................................... 5 2.1 Fibrofolliculomas ........................................................................................................................... 5 2.2 Pulmonary cysts and pneumothorax ............................................................................................ 5 2.2.1 Histology ................................................................................................................................ 5 2.2.2 Prevalence .............................................................................................................................. 5 2.3 Renal cell carcinoma ..................................................................................................................... 6 2.3.1 Histology ................................................................................................................................ 6 2.3.2 Prevalence .............................................................................................................................. 7 2.4 Other clinical manifestations ........................................................................................................ 7 2.4.1 Colorectal polyps and colorectal cancer ................................................................................ 8 2.4.2 Thyroid nodules ..................................................................................................................... 8 2.4.3 Parotid tumours ..................................................................................................................... 8 2.4.4 Other manifestations ............................................................................................................. 8 3. Folliculin gene ..................................................................................................................................... 9 3.1 Identification of the FLCN gene .................................................................................................... 9 3.2 FLCN: mechanism of pathogenesis ............................................................................................... 9 3.2.1 Tumour suppression .............................................................................................................. 9 3.2.2 Happloinsufficiency ................................................................................................................ 9 3.2.3 Dominant negative ............................................................................................................... 10 3.2.4 Compound heterozygosity ................................................................................................... 10 3.3 FLCN mutations ........................................................................................................................... 10 3.3.1 Base substitution mutations ................................................................................................ 11 3.3.2 Deletion mutations .............................................................................................................. 12 3.3.3 Duplication mutations .......................................................................................................... 13 3.3.4 Indel mutations .................................................................................................................... 14 3.3.5 Insertion mutations .............................................................................................................. 14 3.3.6 Base substitutions unlikely to be pathogenic ...................................................................... 15 3.3.7 FLCN variants not associated with BHD ............................................................................... 15 4. Folliculin and its interacting partners ............................................................................................... 17 4.1 Folliculin protein ......................................................................................................................... 17 4.1.1 FLCN structure...................................................................................................................... 18 4.1.2 FLCN-associated post-translational modifications............................................................... 19 4.2. Folliculin-binding proteins ......................................................................................................... 19 1 Copyright Myrovlytis Trust October, 2013 4.2.1 FNIP1 .................................................................................................................................... 19 4.2.2 FNIP2 .................................................................................................................................... 20 4.2.3 Plakophilin-4 ........................................................................................................................ 21 4.2.4 Rpt4 ...................................................................................................................................... 21 4.2.5 Rag proteins ......................................................................................................................... 21 4.3 Expression pattern and cellular localisation of FLCN .................................................................. 22 4.3.1 mRNA ................................................................................................................................... 22 4.3.2 Protein .................................................................................................................................. 22 5. Folliculin-associated signalling pathways ......................................................................................... 24 5.1 mTOR signalling ........................................................................................................................... 24 5.2 HIF signalling and mitochondrial biogenesis ............................................................................... 25 5.3 Stress resistance and autophagy ................................................................................................ 25 5.4 Ras-Raf-MEK-Erk signalling and rRNA synthesis ......................................................................... 26 5.5 JAK/STAT and TGF-β signalling .................................................................................................... 26 5.6 RhoA signalling ............................................................................................................................ 26 5.7 Wnt and Cadherin signalling ....................................................................................................... 27 5.8 Cell Cycle ..................................................................................................................................... 27 5.9 Apoptosis .................................................................................................................................... 27 5.10 Membrane trafficking ............................................................................................................... 28 5.11 Stem cell maintenance and pluripotency ................................................................................. 28 5.12 Ciliogenesis................................................................................................................................ 29 5.13 Matrix Metalloproteinase function........................................................................................... 29 6. Cell lines and model organisms for studying BHD syndrome ........................................................... 30 6.1 UOK-257 cell line ......................................................................................................................... 30 6.2 S. pombe model .......................................................................................................................... 30 6.3 C. elegans model ......................................................................................................................... 31 6.4 Drosophila model ........................................................................................................................ 31 6.5 Mouse models ............................................................................................................................. 31 6.5.1 FLCN mouse models ............................................................................................................. 31 6.5.2 FNIP1 mouse models ........................................................................................................... 32 6.6 Rat model .................................................................................................................................... 32 6.7 Dog model ................................................................................................................................... 32 7. Future Work .....................................................................................................................................