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Introduction
Primary spontaneous pneumothorax [PSP; Online Mendelian Inheritance in Man (OMIM)#173600] occurs in patients without clinically apparent underlying lung disease. Of PSP cases, ~10% are caused by germline mutations in the FLCN gene (1,2), which is known to cause Birt-Hogg-Dube syndrome (BHD; OMIM#135150), an autosomal dominant condition characterized by skin fibrofolliculomas, pulmonary cysts/spontaneous pneumothorax and renal cancers (3,4). FLCN mutation may result in isolated PSP with no skin or renal manifestations, presumably due to an incomplete penetration, as has been reported in multiple previous case studies (1,2,5–7).
Lung cysts are the common pathogenic ground of PSP (8,9). Multiple lung cysts in patients with FLCN mutations are often observed randomly and bilaterally distributed in the lung, particularly in its lower portion (10–13). By contrast, apical bullae are often observed in patients with sporadic PSP without FLCN mutations (14–16). Notably, FLCN mutation-like lung cysts are also observed in a significant portion of non-FLCN mutant sporadic PSP cases (6). Whether these cases are in any way associated with FLCN disruption remains to be elucidated.
The FLCN gene (OMIM#607273) encodes an evolutionarily conserved protein, folliculin, with no apparent functional motif currently recognized. The majority of the pathogenic FLCN mutations, identified to date, resulted in premature truncation of the protein (http://www.skingene-database.com/) (17). FLCN missense mutations and small in-frame deletions were reported to predominantly disrupt protein stability and lead to significant reductions in the expression of FLCN (18). No evidence for a dominant negative effect of FLCN mutants was observed in the transfected cells. Additionally, large intragenic deletions spanning the putative FLCN promoter region have been reported in families with BHD. Luciferase reporter assays demonstrated that a deletion of the putative promoter dramatically reduced the gene expression in vitro (19). In addition, FLCN inactivation caused by promoter methylation has also been detected in types of renal tumor (20,21). This raised the possibility that epigenetic regulation of FLCN may contribute to the pathology of BHD.
The present study selected 71 patients with PSP, who harbored a FLCN mutation-like lung phenotype, however, exhibited no germline and somatic mutations in the FLCN coding regions. Significant variations in the expression of FLCN were observed in the lung cysts of these patients, when compared with those of the patients with BHD and the controls....