Promoter methylation is not associated with FLCN irregulation in lung cyst lesions of primary spontaneous pneumothorax

Ding,Yibing; Zou,Wei; Zhu,Chengchu; Min,Haiyan; Ma,Dehua; Chen,Baofu; Ye,Minhua; Pan,Yanqing; Cao,Lei; Wan,Yueming; Zhu,Qiuxiang; Xia,Haizhen; Zhang,Wenwen; Feng,Ying; Gao,Qian; Yi,Long

doi:10.3892/mmr.2015.4341

Promoter methylation is not associated with FLCN irregulation in lung cyst lesions of primary spontaneous pneumothorax

Authors:
- Yibing Ding
- Wei Zou
- Chengchu Zhu
- Haiyan Min
- Dehua Ma
- Baofu Chen
- Minhua Ye
- Yanqing Pan
- Lei Cao
- Yueming Wan
- Qiuxiang Zhu
- Haizhen Xia
- Wenwen Zhang
- Ying Feng
- Qian Gao
- Long Yi
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Affiliations: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China, Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing, Jiangsu 210093, P.R. China, Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
Published online on: September 21, 2015 https://doi.org/10.3892/mmr.2015.4341
Pages: 7770-7776

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Abstract

Germline mutations in FLCN are responsible for ~10% of patients with primary spontaneous pneumothorax (PSP), characterized by multiple lung cysts in the middle/lower lobes and recurrent pneumothorax. These clinical features are also observed in a substantial portion of patients with sporadic PSP exhibiting no FLCN coding mutations. To assess the potential underlying mechanisms, 71 patients with PSP were selected, including 69 sporadic and 2 familial cases, who bared FLCN mutation‑like lung cysts, however, harbored no FLCN protein‑altering mutations. Notably, in a significant proportion of the patients, FLCN irregulation was observed at the transcript and protein levels. Genetic analyses of the cis‑regulatory region of FLCN were performed by sequencing and multiplex ligation‑dependent probe amplification assay. No inheritable DNA defect was detected, with the exception of a heterozygous deletion spanning the FLCN promoter, which was identified in a family with PSP. This mutation caused a reduction in the expression of FLCN in the lung cysts. Pedigree analysis demonstrated that haploinsufficiency of FLCN was pathogenic. To determine whether epigenetic mechanisms may be involved in the irregulation of FLCN, the promoter methylation status was measured in the remainder of the patients. No evidence of FLCN promoter methylation was demonstrated. The present study suggested that FLCN irregulation in lung cysts of PSP is not associated with promoter methylation.

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