A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax

Abstract

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.

Figure 1

Simplified pedigree of the Finnish family with PSP. HRCT (indicated by an asterisk [*]) was performed for all living family members except individual 25. Affected members (blackened symbols) have ⩾1 bullae on their lungs, detected by HRCT or during surgery (individual 25). Arrows indicate those who had experienced a PSP episode, and numbers indicate those from whom DNA samples were obtained. The presence of bullae could not be confirmed for two individuals who died prior to the study; hence, they were classified as unaffected, even though both had experienced PSP.

Figure 2

HRCT 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.

Figure 3

A 4-bp deletion in exon 4 of the FLCN gene. A, Exon 4 sequence. The deletion is underlined. B, Unaffected control sequence. C, Affected sequence, showing the wild-type and c.733delTCGG alleles.