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A 4-bp Deletion in the Birt-Hogg-Dubé Gene (FLCN) Causes Dominantly Inherited Spontaneous Pneumothorax

2005; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês

10.1086/428455

1537-6605

Jodie N. Painter, Hanna Tapanainen, Mirja Somer, P Tukiainen, Kristiina Aittomäki,

Kidney Stones and Urolithiasis Treatments

Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer. Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer. Primary spontaneous pneumothorax (PSP [MIM 173600]) is a condition in which air is present in the pleural space in the absence of a precipitating event, such as trauma or lung disease. This results in secondary collapse of the lung, either partially or completely, and some degree of hypoxia (Sahn and Heffner Sahn and Heffner, 2000Sahn SA Heffner JE Spontaneous pneumothorax.New Engl J Med. 2000; 342: 868-874Crossref PubMed Scopus (505) Google Scholar). PSP is relatively common, with an incidence between 7.4–18/100,000 for men and 1.2–6/100,000 for women (Melton et al. Melton et al., 1979Melton III, LJ Hepper NGG Offord KP Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974.Am Rev Respir Dis. 1979; 120: 1379-1382PubMed Google Scholar; Bense et al. Bense et al., 1987bBense L Eklund G Wiman LG Onset of symptoms in spontaneous pneumothorax: correlation of physical activity.Eur J Respir Dis. 1987b; 71: 181-186PubMed Google Scholar) and a dose-dependent, increased risk among smokers (Bense et al. Bense et al., 1987aBense L Eklund G Odont D Wiman LG Smoking and the increased risk of contracting spontaneous pneumothorax.Chest. 1987a; 92: 1009-1012Crossref PubMed Scopus (291) Google Scholar). Most cases are sporadic, typically occurring in tall, thin men aged 10–30 years (Primrose Primrose, 1984Primrose WR Spontaneous pneumothorax: a retrospective review of aetiology, pathogenesis and management.Scott Med J. 1984; 29: 15-20PubMed Google Scholar) and generally while at rest. Familial PSP is rarer and usually is inherited as an autosomal dominant condition with reduced penetrance (Abolnik et al. Abolnik et al., 1991Abolnik IZ Lossos IS Zlotogora J Brauer R On the inheritance of primary spontaneous pneumothorax.Am J Med Genet. 1991; 40: 155-158Crossref PubMed Scopus (58) Google Scholar; Morrison et al. Morrison et al., 1998Morrison PJ Lowry RC Nevin NC Familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance.Thorax. 1998; 53: 151-152Crossref PubMed Scopus (41) Google Scholar; Bagchi and Nycyk Bagchi and Nycyk, 2002Bagchi I Nycyk JA Familial spontaneous pneumothorax.Arch Dis Child Fetal Neonatal Ed. 2002; 87: F70Crossref PubMed Google Scholar), although X-linked recessive (Abolnik et al. Abolnik et al., 1991Abolnik IZ Lossos IS Zlotogora J Brauer R On the inheritance of primary spontaneous pneumothorax.Am J Med Genet. 1991; 40: 155-158Crossref PubMed Scopus (58) Google Scholar) and autosomal recessive (Koivisto and Mustonen Koivisto and Mustonen, 2001Koivisto PA Mustonen A Primary spontaneous pneumothorax in two siblings suggests autosomal recessive inheritance.Chest. 2001; 119: 1610-1612Crossref PubMed Scopus (11) Google Scholar) inheritance have also been suggested. The cause of most familial cases is unknown, although PSP may occur in inherited connective tissue disorders, such as Marfan (Dwyer and Troncale Dwyer and Troncale, 1965Dwyer Jr, EM Troncale F Spontaneous pneumothorax and pulmonary disease in the Marfan syndrome: report of two cases and review of the literature.Ann Intern Med. 1965; 62: 1285-1292Crossref PubMed Scopus (31) Google Scholar) and Ehlers-Danlos (Dowton et al. Dowton et al., 1996Dowton SB Pincott S Demmer L Respiratory complications of Ehlers-Danlos type IV.Clin Genet. 1996; 50: 510-514Crossref PubMed Scopus (71) Google Scholar) syndromes and may be associated with particular human leukocyte antigens (Sharpe et al. Sharpe et al., 1980Sharpe IK Ahmad M Braun W Familial spontaneous pneumothorax and HLA antigens.Chest. 1980; 78: 264-268Crossref PubMed Scopus (31) Google Scholar; Yamada et al. Yamada et al., 2003Yamada A Takeda Y Hayashi S Shimizu K Familial spontaneous pneumothorax in three generations and its HLA.Jpn J Thorac Cardiovasc Surg. 2003; 51: 456-458Crossref PubMed Scopus (10) Google Scholar) and alpha 1–antitrypsin deficiency (Daniel and Teba Daniel and Teba, 2000Daniel R Teba L Spontaneous pneumothorax and alpha 1-antitrypsin deficiency.Respir Care. 2000; 45: 327-329PubMed Google Scholar). Although PSP is said to occur without underlying lung disease, almost all patients have subpleural blebs or bullae in their lungs, detectable by computed tomography, thoracoscopy, or thoracotomy (Schramel et al. Schramel et al., 1997Schramel FMNH Postmus PE Vanderschueren RGJRA Current aspects of spontaneous pneumothorax.Eur Respir J. 1997; 10: 1372-1379Crossref PubMed Scopus (241) Google Scholar). Bullae, or localized emphysemalike changes (ELCs), are thin-walled air spaces >1 cm in diameter, distal to terminal bronchioles, and associated with lung-tissue destruction. The development of ELCs is associated with degradation of the elastic fibers of the lung (Fukuda et al. Fukuda et al., 1994Fukuda Y Haraguchi S Tanaka S Yamanaka N Pathogenesis of blebs and bullae of patients with spontaneous pneumothorax: ultrastructural and immunohistochemical studies.Am J Respir Crit Care Med. 1994; 149: A1022Google Scholar) and is thought to involve complex interactions between inflammatory processes, protease-antiprotease and oxidant-antioxidant imbalances, matrix remodeling, and mechanical forces (Suki et al. Suki et al., 2003Suki B Lutchen KR Ingenito EP On the progressive nature of emphysema.Am J Resp Crit Care Med. 2003; 168: 516-521Crossref PubMed Scopus (125) Google Scholar). We recently identified a large Finnish pedigree with a tendency to PSP, which appears to be dominantly inherited (fig. 1). Here, we report the results of a genomewide scan and the identification of a deletion in the folliculin gene (FLCN [MIM 607273; GenBank accession number NM_144997]), also responsible for Birt-Hogg-Dubé syndrome (BHD [MIM 135150]). The family was identified through the index patient (individual 15), who had been referred to the Department of Clinical Genetics at the Helsinki University Central Hospital to be evaluated for a possible connective-tissue disorder. Clinical examinations (conducted independently by K.A. and M.S.) revealed no clinical signs or symptoms of either Marfan syndrome or Ehlers-Danlos syndrome. Alpha 1–antitrypsin deficiency was also excluded. This woman had experienced PSP twice, and her son (individual 25) once. Both individuals had numerous bullae on their lungs (fig. 2). Subsequently, the lungs of 28 additional family members were examined with high-resolution computed tomography (HRCT). Twelve of these family members had between 1 and >30 bullae, 1–6 cm in diameter, randomly situated in the lungs. All individuals with bullae (14 in total) were classified as "affected." One female (individual 7), whose son (individual 23) had bullae and had experienced a PSP episode, had a normal HRCT. PSP history was determined by interviewing family members and was confirmed from hospital records, when available. In total, eight members (including two who had died prior to the study) had each had between one and four PSP episodes. Informed consent was obtained from all participating family members, and the study was approved by the institutional ethics committee.Figure 2HRCT scan of the index patient, who experienced recurrent episodes of PSP. Numerous bullae are visible, seen as clear, black areas. The two largest bullae are indicated with arrows.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Genomic DNA was extracted from blood samples of 25 family members, 13 affected and 12 unaffected. The genome-scan genotyping and scoring was performed by the Finnish Genome Center, University of Helsinki, by use of the Linkage Mapping Set MD10 (Applied Biosystems), with an average intermarker distance of 10 cM. Genotypes were obtained for 371 markers. Two-point LOD scores were calculated with the MLINK program of the FASTLINK package (Cottingham et al. Cottingham et al., 1993Cottingham Jr, RW Idury RM Schaffer AA Faster sequential genetic linkage computations.Am J Hum Genet. 1993; 53: 252-263PubMed Google Scholar), and multipoint and two-point nonparametric linkage (NPL) scores were calculated with GENEHUNTER 2.0 (Kruglyak et al. Kruglyak et al., 1996Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar). For all analyses, inheritance was assumed to be autosomal dominant with reduced penetrance (85%), with a disease allele frequency of 0.001. Allele frequencies for each marker were the same as for the Finnish population (Finnish Genome Center). Evidence of linkage was observed on chromosome 17p11, with single-point linkage peaks at markers D17S1852 (NPL=2.31; P=.006) and D17S798 (LOD=3.43 at recombination fraction [θ]=0.001). Haplotype analysis defined the region shared by all affected family members to ∼34 cM between these two markers. The marker closest to the multipoint linkage peak (NPL=13.45; P=.0009) was D17S1857. Located between D17S1857 and D17S798 is the FLCN gene, responsible for BHD. This gene was a very good positional candidate because of the 50-fold increased risk of PSP in patients with BHD (Zbar et al. Zbar et al., 2002Zbar B Alvord WG Glenn G Turner M Pavlovich CP Schmidt L Walther M Choyke P Weirich G Hewitt SM Duray P Gabril F Greenberg C Merino MJ Toro J Linehan WM Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 393-400PubMed Google Scholar). Primers for the amplification and sequencing of the 14 exons were as detailed by Nickerson et al. (Nickerson et al., 2002Nickerson ML Warren MB Toro JR Matrosova V Glenn G Turner ML Duray P Merino M Choyke P Pavlovich CP Sharma N Walther M Munroe D Hill R Maher E Greenberg C Lerman MI Linehan WM Zbar B Schmidt LS Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with Birt-Hogg-Dubé syndrome.Cancer Cell. 2002; 2: 157-164Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). We found a 4-bp deletion (c.733delTCGG) in exon 4, the first coding exon, of FLCN (fig. 3). (Note that this numbering is in reference to GenBank mRNA sequence NM_144997.) Previous mutations have been annotated in reference to GenBank sequence AF517523, which contains 43 fewer bases of 5′ UTR sequence (the equivalent base in the AF517523 mRNA sequence is nt 690). The 4-bp deletion would cause a frameshift and would result in a TGA termination codon 50 missense amino acids downstream. All family members with bullous lung lesions were heterozygous for this deletion, with the exception of one male (individual 23), who had experienced one PSP episode. Although his mother (individual 7) was a suspected PSP carrier, her normal HRCT result indicated that she did not have the deletion. The apical location of his bullae (bullae typically occur near the lung apex in sporadic cases but are situated randomly in familial ones) strongly suggests that individual 23 experienced PSP as a sporadic event and not through inherited susceptibility. The deletion was not present in unaffected family members or in control samples comprising 100 healthy Finnish individuals and a subgroup of 50 individuals born in the Savo region, an area of early settlement for the Finnish population and the birthplace of the grandparents of the index subject (controls were screened by denaturing high-performance liquid chromotography with a 3500HT WAVE [Transgenomic]). The absence of the deletion in unaffected family members indicates that the penetrance of this mutation in this family is extremely high—apparently 100%—when the presence or absence of bullae is considered as the affection status. Generally, affection status in families with PSP is determined by pneumothorax episodes; hence, penetrance has been suggested to be fairly low, 50% for males and 34% for females (Abolnik et al. Abolnik et al., 1991Abolnik IZ Lossos IS Zlotogora J Brauer R On the inheritance of primary spontaneous pneumothorax.Am J Med Genet. 1991; 40: 155-158Crossref PubMed Scopus (58) Google Scholar). Indeed, had we considered only PSP episodes, penetrance estimates for this family would have been similarly low, particularly for females (two of eight cases). Our results highlight the particular importance of consideration of bullous lung changes in familial PSP. To date, most of the reported mutations in FLCN cause BHD syndrome (Birt et al. Birt et al., 1977Birt AR Hogg GR Dubé J Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.Arch Dermatol. 1977; 113: 1674-1677Crossref PubMed Scopus (557) Google Scholar), a dominantly inherited condition characterized by multiple, benign tumors of the hair follicle (fibrofolliculomas) that typically appear as pale or skin-colored papules over the face, neck, and upper trunk at age ∼20–30 years. In addition, 70% of patients with BHD have pulmonary cysts, 25% experience PSP, and 15%–30% develop diverse types of renal cancer (Choyke et al. Choyke et al., 2003Choyke PL Glenn G Walther MM Zbar B Linehan WM Hereditary renal cancers.Radiology. 2003; 226: 33-46Crossref PubMed Scopus (152) Google Scholar). Other manifestations, particularly colorectal tumors (Khoo et al. Khoo et al., 2002Khoo SK Giraud S Kahnoski K Chen J Motorna O Nickolov R Binet O Lambert D Friedel J Lévy R Ferlicot S Wolkenstein P Hammel P Bergerheim U Hedblad M-A Bradley M Teh BT Nordenskjöld M Richard S Clinical and genetic studies of Birt-Hogg-Dubé syndrome.J Med Genet. 2002; 39: 906-912Crossref PubMed Scopus (165) Google Scholar), have been reported but are not considered to be part of the BHD phenotype (Zbar et al. Zbar et al., 2002Zbar B Alvord WG Glenn G Turner M Pavlovich CP Schmidt L Walther M Choyke P Weirich G Hewitt SM Duray P Gabril F Greenberg C Merino MJ Toro J Linehan WM Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 393-400PubMed Google Scholar; Vincent et al. Vincent et al., 2003Vincent A Farley M Chan E James WD Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules.J Am Acad Dermatol. 2003; 49: 698-705Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). More rarely, somatic mutations, loss of heterozygosity, and methylation of the promotor have been detected in diverse types of sporadic renal and colorectal tumors (Khoo et al. Khoo et al., 2002Khoo SK Giraud S Kahnoski K Chen J Motorna O Nickolov R Binet O Lambert D Friedel J Lévy R Ferlicot S Wolkenstein P Hammel P Bergerheim U Hedblad M-A Bradley M Teh BT Nordenskjöld M Richard S Clinical and genetic studies of Birt-Hogg-Dubé syndrome.J Med Genet. 2002; 39: 906-912Crossref PubMed Scopus (165) Google Scholar, Khoo et al., 2003Khoo SK Kahnoski K Sugimura J Petillo D Chen J Shockley K Ludlow J Knapp R Giraud S Richard S Nordenskjöld M Teh BT Inactivation of BHD in sporadic renal tumors.Cancer Res. 2003; 63: 4583-4587PubMed Google Scholar; da Silva et al. da Silva et al., 2003da Silva NF Gentle D Hensson LB Morton DG Lafif F Maher ER Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer.J Med Genet. 2003; 40: 820-824Crossref PubMed Scopus (65) Google Scholar; Shin et al. Shin et al., 2003Shin J-H Shin Y-K Ku J-L Jeong S-Y Hong S-H Park S-Y Kim W-H Park J-G Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.J Med Genet. 2003; 40: 364-367Crossref PubMed Scopus (26) Google Scholar; Nagy et al. Nagy et al., 2004Nagy A Zoubakov D Stupar Z Kovacs G Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma.Int J Cancer. 2004; 109: 472-475Crossref PubMed Scopus (41) Google Scholar), consistent with the Knudson two-hit model (Knudson Knudson, 1971Knudson AG Mutation and cancer: statistical study of retinoblastoma.Proc Natl Acad Sci USA. 1971; 68: 820-823Crossref PubMed Scopus (5201) Google Scholar), which highlights a potential role for FLCN as a tumor-suppressor gene. The Finnish family under investigation appears to experience only PSP—there are no obvious indications of fibrofolliculomas (or other benign skin tumors) or renal cancer in any member. There are a number of possible explanations for this. The absence of BHD symptoms may be due to the location of the deletion, which occurs in the first coding exon. Whereas almost all mutations in FLCN reported to date are truncating, most BHD- and cancer-associated mutations, with the exception of one somatic exon 4 missense mutation in one colorectal carcinoma (Kahnoski et al. Kahnoski et al., 2003Kahnoski K Khoo SK Nassif NT Chen J Lobo GP Segelov E Teh BT Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours.J Med Genet. 2003; 40: 511-515Crossref PubMed Scopus (26) Google Scholar), occur downstream in the gene. Of familial and sporadic BHD mutations, ∼50% are due to indels in a mutation hotspot in a C8 tract in exon 11. Alternatively, given that less than half of all patients with BHD develop renal cancer and that FLCN mutations are found in only a small number of sporadic renal and colorectal tumors, the cancer phenotype may be determined by other modifier genes that are absent from this particular family or from the Finnish population. It is also possible that the deletion does, in fact, cause BHD in this family and that either the BHD phenotype is very mild and atypical, in that PSP is the predominant manifestation, or the onset of the characteristic skin manifestation is delayed. Fibrofolliculomas typically develop in patients with BHD by age 40 years. Prior to this age, patients are more likely to experience PSP than are older patients, whereas those aged >40 years, particularly affected men, are more likely to develop renal cancers (Zbar et al. Zbar et al., 2002Zbar B Alvord WG Glenn G Turner M Pavlovich CP Schmidt L Walther M Choyke P Weirich G Hewitt SM Duray P Gabril F Greenberg C Merino MJ Toro J Linehan WM Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 393-400PubMed Google Scholar) than are younger patients. The affected members of the family with PSP currently have an age range of 21–83 years (average age 49 years), and all but three affected members are aged ≥44 years. Since this family was initially ascertained as suffering from PSP, the members were not screened for specific BHD manifestations. However, prior to the discovery of the deletion, several family members were independently examined by experienced clinical geneticists (K.A. and M.S.) for the possibility of an unknown syndrome. Skin was examined particularly closely for signs of Ehlers-Danlos syndrome (for which the genotype is skin that is variably thin, hyperextensible, and prone to bruising). Because of the close association of PSP and BHD, Zbar et al. (Zbar et al., 2002Zbar B Alvord WG Glenn G Turner M Pavlovich CP Schmidt L Walther M Choyke P Weirich G Hewitt SM Duray P Gabril F Greenberg C Merino MJ Toro J Linehan WM Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 393-400PubMed Google Scholar) suggested that the BHD gene, then unidentified, might be responsible for some cases of familial PSP and that PSP could be used as a diagnostic criterion for BHD in members of families with BHD. Our results highlight the need to also consider the possibility of BHD in families with PSP, particularly from a clinical perspective, since these patients may be at greater risk of developing renal cancer. We are currently organizing genetic counseling and appropriate examinations, including abdominal scans, for consenting family members. At this point, we can only speculate as to the potential role of FLCN in PSP. The function of the FLCN protein is currently unknown, and it has no known human homologs, although the protein is highly conserved across species (Nickerson et al. Nickerson et al., 2002Nickerson ML Warren MB Toro JR Matrosova V Glenn G Turner ML Duray P Merino M Choyke P Pavlovich CP Sharma N Walther M Munroe D Hill R Maher E Greenberg C Lerman MI Linehan WM Zbar B Schmidt LS Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with Birt-Hogg-Dubé syndrome.Cancer Cell. 2002; 2: 157-164Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). In two animal models, German Shepherd dogs (Lingaas et al. Lingaas et al., 2003Lingaas F Comstock FE Kirkness EF Srensen A Aarskaug T Hitte C Nickerson ML Moe L Schmidt LS Thomas R Breen M Galibert F Zbar B Ostrander EA A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.Hum Mol Genet. 2003; 12: 3043-3053Crossref PubMed Scopus (158) Google Scholar) and the Nihon rat (Okimoto et al. Okimoto et al., 2004Okimoto K Sakurai J Kobayashi T Mitani H Hirayama Y Nickerson ML Warren MB Zbar B Schmidt LS Hino O A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.Proc Nat Acad Sci USA. 2004; 101: 2023-2027Crossref PubMed Scopus (78) Google Scholar), heterozygous mutations cause renal cancer with apparently complete penetrance, and there is evidence of a homozygous lethal effect. In humans, FLCN mRNA is selectively expressed in specific cell types in a number of tissues, including skin, lung, kidney, pancreas, breast, prostate, and cerebellum, which suggests roles in secretion or endocytosis/phagocytosis, in addition to tumor suppression (Warren et al. Warren et al., 2004Warren MB Torres-Cabala CA Turner ML Merino MJ Matrosova VY Nickerson ML Ma W Linehan WM Zbar B Schmidt LS Expression of the Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues.Mod Pathol. 2004; 17: 998-1011Crossref PubMed Scopus (110) Google Scholar). A role in secretion is supported by the findings (1) of Nickerson et al. (Nickerson et al., 2002Nickerson ML Warren MB Toro JR Matrosova V Glenn G Turner ML Duray P Merino M Choyke P Pavlovich CP Sharma N Walther M Munroe D Hill R Maher E Greenberg C Lerman MI Linehan WM Zbar B Schmidt LS Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with Birt-Hogg-Dubé syndrome.Cancer Cell. 2002; 2: 157-164Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar), which suggest a defect in the interaction between epithelial and mesenchymal cells in fibrofolliculomas of patients with BHD, and (2) of Shin et al. (Shin et al., 2003Shin J-H Shin Y-K Ku J-L Jeong S-Y Hong S-H Park S-Y Kim W-H Park J-G Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.J Med Genet. 2003; 40: 364-367Crossref PubMed Scopus (26) Google Scholar), which suggest that cellular proliferation in colorectal cancer is affected by alteration of the extracellular matrix composition. The precise pathogenesis of PSP is also unclear. Bullae are associated with PSP but may be more indicative than causative of underlying changes to the lungs. Whether bullae are the site of rupture—and whether thay have predictive value for the occurrence and recurrence of PSP—are the subjects of considerable debate (see Schramel and Zanen [Schramel and Zanen, 2001Schramel FMNH Zanen P Blebs and/or bullae are of no importance and have no predictive value for recurrences in patients with primary spontaneous pneumothorax.Chest. 2001; 119: 1976-1977Crossref PubMed Scopus (19) Google Scholar]). The development of both bullae and PSP is, however, associated with degradation of elastic fibers in the lung. In emphysema, this degradation is initiated by a protease-antiprotease and an oxidant-antioxidant imbalance that result from an influx of inflammatory cells, particularly macrophages (Barnes Barnes, 2000Barnes PJ Chronic obstructive pulmonary disease.N Engl J Med. 2000; 343: 269-280Crossref PubMed Scopus (1171) Google Scholar). The role of inflammation in the initiation of ELCs is supported by evidence from smokers, who have increased numbers of bronchial macrophages in addition to a 9-fold increased risk among women and a 22-fold increased risk among men of developing pneumothorax (Bense et al. Bense et al., 1987aBense L Eklund G Odont D Wiman LG Smoking and the increased risk of contracting spontaneous pneumothorax.Chest. 1987a; 92: 1009-1012Crossref PubMed Scopus (291) Google Scholar). Within the lung, FLCN mRNA is expressed most strongly in the stromal cells (macrophages and fibroblasts) of the connective tissue and in macrophages within the alveolar space and is expressed moderately in type I pneumocytes, the epithelial cells lining alveoli (Warren et al. Warren et al., 2004Warren MB Torres-Cabala CA Turner ML Merino MJ Matrosova VY Nickerson ML Ma W Linehan WM Zbar B Schmidt LS Expression of the Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues.Mod Pathol. 2004; 17: 998-1011Crossref PubMed Scopus (110) Google Scholar). This expression pattern suggests that the effect of the mutation in lungs may be mediated, particularly through macrophages and possibly through fibroblasts. Both cell types variously secrete a complex mix of factors—including cytokines, chemokines, and proteases—and an imbalance may either induce an inflammatory response even in the absence of an obvious trigger (such as cigarette smoke) or alter matrix degradation and remodeling. In this Finnish family, a 4-bp deletion in FLCN causes inherited PSP. However, determination of the general importance of FLCN in the development of PSP requires further screening of both familial and sporadic patients for mutations in this gene. This, in turn, may help to elucidate the function of the FLCN protein in the lung, in association with PSP and, even more importantly, with generalized emphysema, and perhaps may shed further light on its role in tumorogenesis. We thank the members of the family with PSP for eagerly participating in this study. Two anonymous reviewers improved an earlier draft of this manuscript. This study was supported by a Finnish state grant and the Sigrid Juselius Foundation.