title: Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dubé syndrome.
abstract: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder caused by germline mutations in the FLCN gene, and characterized by skin fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax, and renal neoplasms. Pulmonary manifestations frequently develop earlier than other organ involvements, prompting a diagnosis of BHDS However, the mechanism of lung cyst formation and pathogenesis of pneumothorax have not yet been clarified. Fibroblasts were isolated from lung tissues obtained from patients with BHDS (n = 12) and lung cancer (n = 10) as controls. The functional abilities of these lung fibroblasts were evaluated by the tests for chemotaxis to fibronectin and three-dimensional (3-D) gel contraction. Fibroblasts from BHDS patients showed diminished chemotaxis as compared with fibroblasts from controls. Expression of fibronectin and TGF-β1 was significantly reduced in BHDS fibroblasts when assessed by qPCR Addition of TGF-β1 in culture medium of BHDS lung fibroblasts significantly restored these cells' abilities of chemotaxis and gel contraction. Human fetal lung fibroblasts (HFL-1) exhibited reduced chemotaxis and 3-D gel contraction when FLCN expression was knocked down. To the contrary, a significant increase in chemotactic activity toward to fibronectin was demonstrated when wild-type FLCN was overexpressed, whereas transduction of mutant FLCN showed no effect on chemotaxis. Our results suggest that FLCN is associated with chemotaxis in lung fibroblasts. Together with reduced TGF-β1 expression by BHDS lung fibroblasts, a state of FLCN haploinsufficiency may cause lung fibroblast dysfunction, thereby impairing tissue repair. These may reveal one mechanism of lung cyst formation and pneumothorax in BHDS patients.
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hoshika
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Fariz
authors.initials: F
authors.lastname: Nurwidya
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.|Pneumothorax Research Center and Division of Thoracic Surgery, Nissan Tamagawa Hospital, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.|Pneumothorax Research Center and Division of Thoracic Surgery, Nissan Tamagawa Hospital, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ebana
authors.affiliation: Biomedical Research Center, Laboratory of Proteomics and Biomolecular Science, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kikkawa
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.|The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishino
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Divisions of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan kseyama@juntendo.ac.jp.|The Study Group of Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
mesh_terms: D000328:Adult; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics* / Q000473:pathology; D002633:Chemotaxis / Q000502:physiology; D003560:Cysts / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D018095:Germ-Line Mutation; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000175:diagnosis / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D011030:Pneumothorax / Q000175:diagnosis / Q000235:genetics / Q000601:surgery; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000175:diagnosis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins
keywords: Chemotaxis; TGF‐β1; fibroblast; folliculin; haploinsufficiency