Birt–Hogg–Dubé (BHD) syndrome (OMIM 135150) is an autosomal, dominantly inherited, monogenic condition, characterised by the development of benign skin tumours (fibrofolliculomas) on the face 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).

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 the inactivated gene in individuals with BHD Syndrome. The FLCN gene codes for a protein of unknown function called folliculin (FLCN).

BHD syndrome was first described in 1977 by three Canadian doctors – Birt, Hogg and Dubé (Birt et al, 1977). 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).

BHD syndrome may be considered one of the hamartoma syndromes.  Hamartoma syndromes are dominantly inherited, predispose to cancer that affects multiple organs, and result in the development of benign tumours, made up from the cell type from which they arise. This association has arisen since BHD syndrome shares many clinical features (i.e. hamartomas, mucosal fibromas, and epithelial tumourigenesis) with other hamartoma syndromes, like 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; Toro et al, 2002). PTEN, LKB1, and TSC1/2 are members of the mammalian target of rapamycin (mTOR) signalling pathway. The mTOR pathway is a key regulator of cell growth and proliferation (Hay and Sonenberg, 2004) and an increasing amount of evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes (Landau et al, 2009). The mTOR signalling pathway integrates signals from nutrients and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism (Laplante and Sabatini, 2009).

Loss of gene function is known to be involved in the deregulation of the mTOR signalling pathway and is implicated as a contributing factor to various human diseases, especially various types of cancer (Harris and Lawrence JC, 2003; Fingar and Blenis, 2004; Sarbassov et al, 2005). Current research suggests that the FLCN protein also has a tumour suppressor function and is implicated in the mTOR signalling pathway (Baba et al, 2006; Wang et al, 2009; Baba et al, 2009).

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