Mutation analysis of the FLCN gene in Chinese patients with sporadic and amilial isolated primary spontaneous pneumothorax
Department of Pathology, Nanjing University Medical School, Nanjing, Jiangsu, China. Clinical Genetics
(Impact Factor: 3.93).
08/2008; 74(2):178-83. DOI: 10.1111/j.1399-0004.2008.01030.x
Primary spontaneous pneumothorax (PSP) is a common manifestation of Birt-Hogg-Dubé syndrome caused by folliculin gene (FLCN) mutation, which is also found in isolated familial PSP cases. A complete genetic analysis of FLCN was performed in 102 unrelated Chinese patients with isolated PSP and 21 of their family members. Three novel mutations (c.924_926del, c.1611_1631del and c.1740C>T) and a previously reported mutation (c.1733insC) were identified in five familial and five sporadic PSP patients. Of the 21 family members of patients with PSP including 3 previous considered as sporadic, 4 (19%) had history of at least one episode of PSP and 9 (43%) were FLCN mutant carriers without PSP. Seven of the nine (78%) mutant carriers had pulmonary cysts detected by high-resolution computed tomography (HRCT). Although c.924_926del and c.1611_1631del were found in eight patients from the same geographic district, haplotype analysis demonstrated that they did not share the same affected haplotype, thus excluding common ancestry. This study first demonstrates that FLCN mutation contributes to not only familial but also 'apparently sporadic' patients with isolated PSP. It suggests that mutation analysis and HRCT scan may be recommended for first-degree family members of PSP patients with FLCN mutations, irrespective of their family history status of PSP.
Available from: Rongrong Chen
- "Isolated pulmonary cysts with or without pneumothorax were reported in a large Finnish family with 24 affected members carrying a 4-bp deletion in exon (Painter et al., 2005). Ren et al. (2008) analyzed 102 unrelated Chinese patients with isolated spontaneous pneumothorax and 21 of their family members, and found that 10 patients and 13 of their family members were with FLCN mutations. Like many other genetic diseases, no correlation has been established between genotype and phenotype for BHD patients. "
Available from: Chenggang Li
- "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.
Available from: Pieter Edsge Postmus
- "The literature on the incidence of BHD syndrome in adults with PSP is very limited. Ren and colleagues found a prevalence of 9.8% in 102 apparently adult SP patients . In a pilot study among 40 apparently primary SP patients we found a pathogenic FLCN mutation in 3 (7.5%) "
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Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited disorder caused by germline mutations in the folliculin (FLCN) gene. Clinical manifestations of BHD include skin fibrofolliculomas, renal cell cancer, lung cysts and (recurrent) spontaneous pneumothorax (SP). All clinical manifestations usually present in adults > 20 years of age.
Two non-related patients with (recurrent) pneumothorax starting at age 14 accompanied by multiple basal lung cysts on thoracic CT underwent FLCN germline mutation analysis. A pathogenic FLCN mutation was found in both patients confirming suspected BHD. The family history was negative for spontaneous pneumothorax in both families.
Although childhood occurrence of SP in BHD is rare, these two cases illustrate that BHD should be considered as cause of SP in children.
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