Birt–Hogg–Dubé (BHD) syndrome (OMIM 135150) is an autosomal, dominantly inherited, monogenic condition, characterised by the development of fibrofolliculomas (benign skin tumours) on the face, head and upper torso, pulmonary cysts and pneumothorax (collapsed lung), and predisposition to kidney cancers with clear cell, chromophobic or oncocytic features (Birt et al., 1977). The clinical manifestations of BHD syndrome are discussed in Section 1.
BHD syndrome was first described in 1977 by three Canadian doctors – Birt, Hogg and Dubé (Birt et al., 1977). In 2001, a BHD-associated gene locus was localised to chromosome 17p11.2 (Khoo et al., 2001; Schmidt et al., 2001) and a novel gene, Folliculin (FLCN), was subsequently identified as being inactivated in individuals with BHD syndrome (Nickerson et al., 2002). The FLCN gene codes for a protein called Folliculin (FLCN), which has a putative tumour suppressor function (Vocke et al., 2005; Hudon et al., 2010; Hong et al., 2010a; Cash et al., 2011). To date, approximately 200 families have been reported with pathogenic FLCN mutations (Schmidt et al., 2005; Graham et al., 2005; Toro et al., 2008; Misago et al., 2008; Frohlich et al., 2008; Leter et al., 2008; Woodward et al., 2008; Kunogi et al., 2010). As of February 2011, 132 different FLCN mutations have been identified (www.lovd.nl/flcn, Lim et al., 2010), 91 of which are described as pathogenic. The Folliculin gene and its mutations are described in Section 2.
BHD syndrome shares many clinical features with hamartoma syndromes (Toro et al., 2002). Hamartoma syndromes are dominantly inherited, predispose to cancer that affects multiple organs, and result in the development of benign tumours. Such syndromes include Cowden syndrome, Peutz-Jeghers syndrome, and Tuberous Sclerosis complex (TSC), caused by inactivation of the tumour suppressor genes PTEN, LKB1 and TSC1/TSC2 respectively (Liaw et al., 1997; Marsh et al., 1999).
Folliculin and its two known interacting proteins – FNIP1 and FNIP2 – are discussed in Section 3 (Baba et al., 2006; Hasumi et al., 2008; Takagi et al., 2008). Research has demonstrated that FNIP1 and FNIP2 along with 5’-AMP-activated protein kinase (AMPK), are able to phosphorylate FLCN (Baba et al., 2006; Hasumi et al., 2008; Takagi et al., 2008). FLCN has been implicated in numerous signalling pathways including mTOR and AMPK signalling (Baba et al., 2006; Baba et al., 2008; Wang et al., 2010), HIF signalling (Preston et al., 2010), TGF-β signalling (Hong et al., 2010a; Cash et al., 2011) and the JAK-STAT signalling pathway (Singh et al., 2006). The function of FLCN and its role in these pathways is discussed in detail in Section 4.