What is BHD?

Our BHD literature review, “What is BHD?”, in the “For Researchers” section of BHDSyndrome.org has been updated. This is the first major update since March 2011, and incorporates all literature published since then, including Tsun et al., 2013, who earlier this week reported that FLCN activates mTORC1 activity, and will be the subject of next week’s blog. This review is aimed at researchers and clinicians, and is available in html format, and as a pdf. We will be updating these pages on our website on a monthly basis, to ensure that it remains an up to date and useful resource for those interested in BHD.

In the Introduction section we now include a summary of published BHD families. Since we have only included those studies where we are certain cases are not reported elsewhere in the literature, and BHD is often misdiagnosed, our estimate of 426 families worldwide is likely to be low.

Section 2 describes the clinical manifestations of BHD. As well as updating the literature regarding the skin, lung and kidney symptoms of BHD, information about other clinical manifestations has been updated, with parotid tumours being given more prominence as there are now at least eight reported cases of BHD patients developing these tumours.

Section 3 reviews research about the Folliculin gene and its role in BHD. Discussion of the mechanisms through which FLCN mutations might cause BHD has been expanded to include happloinsufficiency, dominant negative function and compound heterozygosity in addition to tumour suppression. Additionally, our list of published FLCN mutations has been updated to correspond with the LOVD database curated by Dr Derek Lim (Lim et al., 2010). For clarity, single nucleotide substitutions that are not associated with BHD or are unlikely to be pathogenic are now listed separately from the single base substitutions that are likely to be pathogenic.

Since the last update, the structure of the C-terminal end of Folliculin has been published (Nookala et al., 2012), and additional binding partners for FLCN have been found. For clarity, information about Folliculin expression and cellular localisation has been split into mRNA and protein sections. All this information can be found in Section 4 of “What is BHD?”

The biggest change between the old and new versions of “What is BHD?” is seen in Section 5, which describes the signalling pathways and biological processes that FLCN has been linked to. This section has been added to and rearranged and now includes information about FLCN’s role in mTOR signalling; HIF signalling and mitochondrial biogenesis; stress resistance and autophagy; Ras-Raf-MEK-Erk signalling and rRNA synthesis; JAK/STAT and TGF-β signalling; RhoA signalling; Wnt and Cadherin signalling; cell cycle; apoptosis; membrane trafficking; stem cell maintenance and pluripotency; ciliogenesis; and matrix metalloproteinase function.

Our interactive FLCN signalling diagram was previously embedded in Section 5 of “What is BHD?” but is now a standalone resource, which can be found in our Resources section. This is currently being redesigned, and will be launched in a few weeks.

Section 6 describes the cell lines and animal models used for studying BHD syndrome. Information about the UOK-257 cell line, the C. elegans model (Gharbi et al., 2013), the Drosophila model (Liu et al., 2013), and FNIP1 knock out mouse models (Baba et al., 2012, Park et al., 2012) has been added to this section.

Section 7 discusses some possible future directions for BHD research, including a discussion of encouraging studies showing that SSH2 is a synthetic lethal target of FLCN (Lu et al., 2013), and that a gene therapy approach has been successfully used to reinstate FLCN function in FLCN-null cells (Wong and Harbottle, 2013), which might both prove to be viable BHD therapies in the future.

If you have any comments or suggestions regarding this update or any other aspect of the website, please do not hesitate to email us at contact@BHDSyndrome.org or fill in our feedback form.


  • Baba M, Keller JR, Sun HW, Resch W, Kuchen S, Suh HC, Hasumi H, Hasumi Y, Kieffer-Kwon KR, Gonzalez CG, Hughes RM, Klein ME, Oh HF, Bible P, Southon E, Tessarollo L, Schmidt LS, Linehan WM, & Casellas R (2012). The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. Blood, 120 (6), 1254-61 PMID: 22709692
  • Gharbi H, Fabretti F, Bharill P, Rinschen MM, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU (2013). Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner. Aging cell, 12 (4), 593-603 PMID: 23566034
  • Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, & Maher ER (2010). A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Human mutation, 31 (1) PMID: 19802896
  • Liu W, Chen Z, Ma Y, Wu X, Jin Y, & Hou S (2013). Genetic characterization of the Drosophila birt-hogg-dubé syndrome gene. PloS one, 8 (6) PMID: 23799055
  • Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A, Nagy Z, & Maher ER (2013). Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene PMID: 23416984
  • Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, & Blundell TL (2012). Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open biology, 2 (8) PMID: 22977732
  • Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G, & Iritani BM (2012). Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity, 36 (5), 769-81 PMID: 22608497
  • Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, & Sabatini DM (2013). The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1. Molecular cell PMID: 24095279
  • Wong SP, & Harbottle RP (2013). Genetic modification of dividing cells using episomally maintained S/MAR DNA vectors. Molecular therapy. Nucleic acids, 2 PMID: 23941867

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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