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.

Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

“…Pneumothorax was observed in 5 out of 17 (29.4%) members who carried a mutation in this family, which was similar to a prevalence of 29% in a previous report (21). However, according to Jodie et al, the bullous lung changes observed on chest CT scan should be considered as the pulmonary manifestation of this syndrome (15). The multiple pulmonary cysts observed in mutation carriers III-2 and III-3 support this idea.…”

“…The multiple pulmonary cysts observed in mutation carriers III-2 and III-3 support this idea. Therefore, it was difficult to calculate the accurate frequency of pulmonary involvement in this family without CT imaging; several previous reports with different sample sizes showed that the number ranges from 70% to 100% (15,(22)(23)(24). Late onset may also play a role in the reported difference in pulmonary involvement.…”

A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene

“…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, 2005Gunji 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.…”

“…Germline mutations in the folliculin gene (FLCN) were first identified in BHD patients in 2002 (Nickerson et al, 2002). In addition, FLCN mutations have also been discovered in patients with familial Primary Spontaneous Pneumothorax (PSP; MIM# 173600) and cases presenting with familial clear cell renal carcinoma (FcRCC) in whom other features of BHD have not been noted (Frohlich et al, 2008;Graham et al, 2005;Gunji et al, 2007;Painter et al, 2005;Ren et al, 2008;Woodward et al, 2008) …”

Autosomal Recessively Inherited Familial Primary Spontaneous Pneumothorax: A Large Family with Frequent Consanguineous Marriages

“…Even though the male gender is dominantly affected by FPSP, it can still be seen in both genders. 6,7,10,11 The aim of this study was to investigate the demographic, clinical, laboratory, radiological and hereditary characteristics of 8 PSP cases within an extended family in which frequent consanguineous marriages are seen.…”