Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells

Okamoto, Shouichi; Ebana, Hiroki; Kurihara, Masatoshi; Mitani, Keiko; Kobayashi, Etsuko; Hayashi, Takuo; Sekimoto, Yasuhito; Nishino, Koichi; Otsuji, Mizuto; Kumasaka, Takashi; Takahashi, Kazuhisa; Seyama, Kuniaki

doi:10.1038/s41598-021-90184-9

Cited by 4 publications

(5 citation statements)

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“…adhesion junction protein VE-cadherin, ZO-1 a linker protein and β-catenin one of components of cell–cell adhesion machinery [ 32 – 36 ]. We demonstrated that HPMC successfully form tight and adhesion junctions which is in concordance with previously published works using HPMC monolayer as a model to assess the functional integrity of the peritoneum [ 37 ] and pathogenesis of pneumothorax [ 38 ] underlying the importance of our established in vitro system. We assessed the permeability of our system and detected decrease in permeability of 3D organotypic co-culture model of pleura compared to collagen matrix with fibroblasts and polymer mesh without cells up to age of 3 days after complete construction of 3D co-culture model.…”

Section: Discussionsupporting

confidence: 89%

Novel 3D organotypic co-culture model of pleura

et al. 2022

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Pleural mesothelial cells are the predominant cell type in the pleural cavity, but their role in the pathogenesis of pleural diseases needs to be further elucidated. 3D organotypic models are an encouraging approach for an in vivo understanding of molecular disease development. The aim of the present study was to develop a 3D organotypic model of the pleural mesothelium. Specimens of human pleura parietalis were obtained from patients undergoing surgery at the University Hospital Leipzig, Germany. 3D co-culture model of pleura was established from human pleural mesothelial cells and fibroblasts. The model was compared to human pleura tissue by phase-contrast and light microscopy, immunochemistry and -fluorescence as well as solute permeation test. Histological assessment of the 3D co-culture model displayed the presence of both cell types mimicking the morphology of the human pleura. Vimentin and Cytokeratin, PHD1 showed a similar expression pattern in pleural biopsies and 3D model. Expression of Ki-67 indicates the presence of proliferating cells. Tight junctional marker ZO-1 was found localized at contact zones between mesothelial cells. Each of these markers were expressed in both the 3D co-culture model and human biopsies. Permeability of 3D organotypic co-culture model of pleura was found to be higher for 70 kDa-Dextran and no significant difference was seen in the permeability for small dextran (4 kDa). In summary, the presented 3D organoid of pleura functions as a robust assay for pleural research serving as a precise reproduction of the in vivo morphology and microenvironment.

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Section: Discussionsupporting

confidence: 89%

Novel 3D organotypic co-culture model of pleura

et al. 2022

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“…Haploinsufficiency at FLCN has also been reported in BHDS manifestations 10,11 . FLCN protein is similar to DENN domain proteins, though its exact function is unknown 12 .…”

Section: Introductionmentioning

confidence: 90%

“…BHDS renal tumours exhibit loss of heterozygosity (LOH), suggesting a tumour suppression role of FLCN in kidney 9 . Haploinsufficiency at FLCN has also been reported in BHDS manifestations 10,11 . FLCN protein is similar to DENN domain proteins, though its exact function is unknown 12 .…”

Section: Introductionmentioning

confidence: 90%

Genetic Insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations in FLCN

Ray

Chattopadhyay

Bera

et al. 2021

Preprint

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BackgroundBirt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma. Here, we comprehensively studied germline mutations in BHDS patients and asymptomatic members from 15 Indian families.MethodsTargeted amplicon NGS and Sanger sequencing was performed to detect germline mutations at FLCN in 31 clinically diagnosed patients and 74 asymptomatic family members. Functional effects and protein-protein interaction of FLCN variants were evaluated in-silico and molecular docking method. Family-based association study between pathogenic mutations and BHDS was also performed. Germline mutations at genes associated with phenotypically similar diseases were also addressed in few families.ResultsSix different types of pathogenic FLCN mutations were observed in the patients. Two of them: 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and splice acceptor mutation (c.1301-1G>A), were novel mutations. Two unreported Clinvar pathogenic mutations: stop-gain (c.634C>T) and 4-nucleotide duplication (c.1329_1332dupAGCC), and known mutations: hotspot mutation (c.1285delC) and splice donor mutations (c.1300+1G>A) were also detected. All these mutations greatly affected the protein stability and FLCN-FNIP2 protein interaction. Family-based association studies suggested pathogenic FLCN mutations are significantly associated with BHDS. Two pathogenic SNPs, rs1801133 and rs138189536, at MTHFR, associated with Homocystinuria, were found in one family.ConclusionPathogenic mutations at FLCN may play key roles in deregulating metabolic pathways leading to disease pathogenesis. Instead of FLCN mutations, MTHFR pathogenic SNPs were also detected in clinically diagnosed BHDS patients, therefore, genetic evaluation is necessary to avoid confounding diagnosis.

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“…FLCN encodes a protein known as folliculin [ 4 ], which is believed to act as a tumor suppressor, based on Knudson’s two-hit hypothesis, in BHDS-associated renal tumors [ 5 , 6 ]. However, unlike renal tumors, no somatic variants or loss of heterozygosity has been detected in either skin [ 7 ] or pulmonary lesions, suggesting that haploinsufficiency can induce the phenotypes observed in these tissues [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic features of 334 Asian patients with Birt–Hogg–Dubé syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax

et al. 2023

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Background The clinical pulmonary manifestations and genetic features of Birt–Hogg–Dubé syndrome (BHDS) in Asian patients remained unclear. We aimed to clarify the clinical features of BHDS-associated pneumothorax (PTX) and retrospectively investigate potential contributing factors in the largest Asian cohort to date. Methods We reviewed the clinical and genetic data collected in 2006–2017, from the BHDS patients who were Asian and presented with pulmonary cysts with or without a history of PTX. Results Data from 334 (41.3% males; 58.7% females) patients from 297 unrelated families were reviewed. Among them, 314 (94.0%) patients developed PTX. The median age at the first occurrence of PTX was 32 years, which was significantly lower in males (P = 0.003) and patients without notable skin manifestations (P < 0.001). Seventy-six (24.2%) patients experienced their first PTX episode before the age of 25 years. PTX simultaneously occurred in the bilateral lungs of 37 (11.8%) patients. Among 149 patients who had their first PTX episode at least 10 years before BHDS diagnosis, PTX occurred more frequently in males (P = 0.030) and light smokers than in nonsmokers (P = 0.014). The occurrence of PTX peaked in the early 30s and gradually decreased with age but remained high in females (P = 0.001). We identified 70 unique FLCN germline variants, including duplications (46.4%), substitutions (7.1%), insertions/deletions (30.0%), and variants affecting splicing (12.5%). Approximately 80% of Asian patients suspected of having BHDS could be genetically diagnosed by examining FLCN exons 7, 9, 11, 12, and 13. No apparent genotype–phenotype correlation regarding pulmonary manifestations was identified. Conclusions Our findings indicate that sex, smoking history, and skin manifestations at BHDS diagnosis significantly influence the clinical features of BHDS-associated PTX. These findings may contribute to the appropriate management and treatment of BHDS-associated PTX.

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Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells

Cited by 4 publications

References 51 publications

Novel 3D organotypic co-culture model of pleura

Novel 3D organotypic co-culture model of pleura

Genetic Insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations in FLCN

Clinical and genetic features of 334 Asian patients with Birt–Hogg–Dubé syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax

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