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Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome

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 or...

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Autores principales: Hoshika, Yoshito, Takahashi, Fumiyuki, Togo, Shinsaku, Hashimoto, Muneaki, Nara, Takeshi, Kobayashi, Toshiyuki, Nurwidya, Fariz, Kataoka, Hideyuki, Kurihara, Masatoshi, Kobayashi, Etsuko, Ebana, Hiroki, Kikkawa, Mika, Ando, Katsutoshi, Nishino, Koichi, Hino, Okio, Takahashi, Kazuhisa, Seyama, Kuniaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112502/
https://www.ncbi.nlm.nih.gov/pubmed/27905298
http://dx.doi.org/10.14814/phy2.13025
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author Hoshika, Yoshito
Takahashi, Fumiyuki
Togo, Shinsaku
Hashimoto, Muneaki
Nara, Takeshi
Kobayashi, Toshiyuki
Nurwidya, Fariz
Kataoka, Hideyuki
Kurihara, Masatoshi
Kobayashi, Etsuko
Ebana, Hiroki
Kikkawa, Mika
Ando, Katsutoshi
Nishino, Koichi
Hino, Okio
Takahashi, Kazuhisa
Seyama, Kuniaki
author_facet Hoshika, Yoshito
Takahashi, Fumiyuki
Togo, Shinsaku
Hashimoto, Muneaki
Nara, Takeshi
Kobayashi, Toshiyuki
Nurwidya, Fariz
Kataoka, Hideyuki
Kurihara, Masatoshi
Kobayashi, Etsuko
Ebana, Hiroki
Kikkawa, Mika
Ando, Katsutoshi
Nishino, Koichi
Hino, Okio
Takahashi, Kazuhisa
Seyama, Kuniaki
author_sort Hoshika, Yoshito
collection PubMed
description 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.
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spelling pubmed-51125022016-11-25 Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome Hoshika, Yoshito Takahashi, Fumiyuki Togo, Shinsaku Hashimoto, Muneaki Nara, Takeshi Kobayashi, Toshiyuki Nurwidya, Fariz Kataoka, Hideyuki Kurihara, Masatoshi Kobayashi, Etsuko Ebana, Hiroki Kikkawa, Mika Ando, Katsutoshi Nishino, Koichi Hino, Okio Takahashi, Kazuhisa Seyama, Kuniaki Physiol Rep Original Research 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. John Wiley and Sons Inc. 2016-11-15 /pmc/articles/PMC5112502/ /pubmed/27905298 http://dx.doi.org/10.14814/phy2.13025 Text en © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Hoshika, Yoshito
Takahashi, Fumiyuki
Togo, Shinsaku
Hashimoto, Muneaki
Nara, Takeshi
Kobayashi, Toshiyuki
Nurwidya, Fariz
Kataoka, Hideyuki
Kurihara, Masatoshi
Kobayashi, Etsuko
Ebana, Hiroki
Kikkawa, Mika
Ando, Katsutoshi
Nishino, Koichi
Hino, Okio
Takahashi, Kazuhisa
Seyama, Kuniaki
Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title_full Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title_fullStr Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title_full_unstemmed Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title_short Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome
title_sort haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with birt–hogg–dubé syndrome
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112502/
https://www.ncbi.nlm.nih.gov/pubmed/27905298
http://dx.doi.org/10.14814/phy2.13025
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