Novel mutations in the folliculin (FLCN) gene associated with spontaneous pneumothorax

Pulmonary Division, University Hospital of Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.
European Respiratory Journal (Impact Factor: 7.64). 06/2008; 32(5):1316-20. DOI: 10.1183/09031936.00132707
Source: PubMed


Spontaneous pneumothorax is mostly sporadic but may also occur in families with genetic disorders, such as Birt-Hogg-Dubé syndrome, which is caused by mutations in the folliculin (FLCN) gene. The aim of the present study was to investigate the presence and type of mutation in a Swiss pedigree and in a sporadic case. Clinical examination, lung function tests and high-resolution computed tomography were performed. All coding exons and flanking intronic regions of FLCN were amplified by PCR and directly sequenced. The amount of FLCN transcripts was determined by quantitative real-time RT-PCR. Two novel mutations in FLCN were identified. Three investigated family members with a history of at least one spontaneous pneumothorax were heterozygous for a single nucleotide substitution (c.779G>A) that leads to a premature stop codon (p.W260X). Quantitative real-time RT-PCR revealed a reduction of FLCN transcripts from the patient compared with an unaffected family member. DNA from the sporadic case carried a heterozygous missense mutation (c.394G>A). Lung function of this patient was normal and computed tomography showed similar bilateral cysts, as observed in the two members of the unrelated Swiss family. Mutations in the folliculin gene are associated with cystic lung lesions in an otherwise morphological normal lung and predispose to spontaneous pneumothorax.

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Available from: Christina Zeitz, Oct 27, 2015
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    • "It is estimated that 35% of BHD patients have a family history of pneumothorax (Gupta et al. 2013). Germline BHD mutations are the most common cause of hereditary pneumothorax even in patients without evidence of renal or skin lesions (Painter et al. 2005; Frohlich et al. 2008; Ren et al. 2008; Sundaram et al. 2009). Cystic lung disease in BHD patients has been observed in utero (Sundaram et al. 2009) and pneumothorax as young as age 16 (Furuya and Nakatani 2013). "
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    ABSTRACT: Germline loss-of-function BHD mutations cause cystic lung disease and hereditary pneumothorax, yet little is known about the impact of BHD mutations in the lung. Folliculin (FLCN), the product of the Birt–Hogg–Dube (BHD) gene, has been linked to altered cell–cell adhesion and to the AMPK and mTORC1 signaling pathways. We found that downregulation of FLCN in human bronchial epithelial (HBE) cells decreased the phosphorylation of ACC, a marker of AMPK activation, while downregulation of FLCN in small airway epithelial (SAEC) cells increased the activity of phospho-S6, a marker of mTORC1 activation, highlighting the cell type–dependent functions of FLCN. Cell–cell adhesion forces were significantly increased in FLCN-deficient HBE cells, consistent with prior findings in FLCN-deficient human kidney-derived cells. To determine how these altered cell–cell adhesion forces impact the lung, we exposed mice with heterozygous inactivation of Bhd (similarly to humans with germline inactivation of one BHD allele) to mechanical ventilation at high tidal volumes. Bhd+/− mice exhibited a trend (P = 0.08) toward increased elastance after 6 h of ventilation at 24 cc/kg. Our results indicate that FLCN regulates the AMPK and mTORC1 pathways and cell–cell adhesion in a cell type–dependent manner. FLCN deficiency may impact the physiologic response to inflation-induced mechanical stress, but further investigation is required. We hypothesize that FLCN-dependent effects on signaling and cellular adhesion contribute to the pathogenesis of cystic lung disease in BHD patients.
    08/2014; 2(8). DOI:10.14814/phy2.12107
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    • "and was cloned in 2002 [13], lead to an autosomal dominant disease associated with fibrofolliculomas (benign skin tumors), cystic lung disease, which can result in spontaneous pneumothorax (lung collapse), and renal cell carcinomas (RCC), which are most often of the chromophobe subtype. The penetrance of these phenotypes is incomplete: 15–30% of BHD patients develop RCC [14], and families have been reported in which cystic lung disease and pneumothorax occur in the absence of renal or skin manifestations [15], [16], [17], [18]. Nearly all germline BHD mutations are truncating, and RCC from BHD patients exhibit loss of heterozygosity of chromosome 17p [14], [19], [20], consistent with the hypothesis that BHD is a tumor suppressor gene. "
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    ABSTRACT: Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues. Surprisingly, we found that downregulation of FLCN leads to increased cell-cell adhesion in functional cell-based assays and disruption of cell polarity in a three-dimensional lumen-forming assay, both of which are phenocopied by downregulation of p0071. These data indicate that the FLCN-p0071 protein complex is a negative regulator of cell-cell adhesion. We also found that FLCN positively regulates RhoA activity and Rho-associated kinase activity, consistent with the only known function of p0071. Finally, to examine the role of Flcn loss on cell-cell adhesion in vivo, we utilized keratin-14 cre-recombinase (K14-cre) to inactivate Flcn in the mouse epidermis. The K14-Cre-Bhd(flox/flox) mice have striking delays in eyelid opening, wavy fur, hair loss, and epidermal hyperplasia with increased levels of mammalian target of rapamycin complex 1 (mTORC1) activity. These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling, with broad implications for the role of cell-cell adhesion molecules in the pathogenesis of human disease, including emphysema and renal cell carcinoma.
    PLoS ONE 11/2012; 7(11):e47842. DOI:10.1371/journal.pone.0047842 · 3.23 Impact Factor
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    • "The ongoing maintenance of the database is guaranteed by the consortium. The database lists previously published point mutations, deletions, duplications and splice site mutations in the FLCN gene (Bessis et al., 2006; Cho et al., 2008; Frohlich et al., 2008; Gad et al., 2007,Graham et al., 2005; Gunji et al., 2007; Imada et al., 2009; Kawasaki et al., 2005; Khoo et al., 2002; Kim et al., 2008; Lamberti et al., 2005; Leter et al., 2008; Murakami et al., 2007; Nickerson et al., 2002; Painter et al., 2005; Palmirotta et al., 2008; Ren et al., 2008; Schmidt et al., 2005; Toro et al., 2008; van Steensel et al., 2007; Woodward et al., 2008). In addition 10 previously unpublished novel mutations/variants are included. "
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    ABSTRACT: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised by the presence of facial fibrofolliculomas, pulmonary cysts which may be associated with spontaneous pneumothorax and renal tumours. Germline mutations in the gene Folliculin (FLCN) were first identified in BHD patients in 2002. In addition FLCN mutations have also been described in families with isolated primary spontaneous pneumothorax (PSP) and also familial clear cell renal carcinomas (FcRCC). We have established a locus-specific database based on the Leiden Open (source) Variation Database (LOVD) software. The version of the database contains 60 previously published mutations and 10 previously unpublished novel germline FLCN mutations. The mutations are comprised of deletions (44.3%), substitutions (35.7%), duplications (14.3%) and deletion/insertions (5.7%). The database is accessible online at
    Human Mutation 01/2010; 31(1):E1043-51. DOI:10.1002/humu.21130 · 5.14 Impact Factor
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