Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116061 | GEO | 2018/06/21
REPOSITORIES: GEO
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Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive phosphoproteomic profiles of FLCN-POS and FLCN-NEG human tumor cells (UOK257). UOK257 misses the folliculin (FLCN) gene, whereas UOK 257-2 harbours a lentiviral rescue of the FLCN gene. Experiment performed in duplicate. This data set is linked to PXD021346 that describes phosphoproteomics results for human renal tubular epithelial cells (RPTEC/TERT1).
2022-07-11 | PXD030237 | Pride
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Project description:Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in FLCN. Here, we describe an oncocytic tumor in the thyroid harboring pathogenic FLCN alterations. The tumor showed indolent clinical behavior and was composed of solid sheets of oncocytic cells with abundant granular eosinophilic cytoplasm. Mitochondrial genome sequencing demonstrated preserved mitochondrial architecture without pathogenic mitochondrial DNA alterations. In vitro functional studies demonstrated that FLCN deficiency was associated with global attenuation of canonical phosphorylation–dependent signaling pathways, activation of AMPK signaling, upregulation of GPNMB, and increased expression of the mitochondrial marker Prohibitin, consistent with a cellular stress response. RNA sequencing analyses further indicated coordinated suppression of multiple metabolic and signaling pathways. These findings suggest that an FLCN-mutated oncocytic tumor in the thyroid represents a biologically distinct subset driven primarily by compensatory mitochondrial biogenesis rather than by classical oncogenic signaling activation or primary mitochondrial genome instability.
2026-04-15 | GSE327395 | GEO
Project description:Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint novel prognostic biomarkers.
2021-02-11 | PXD021346 | Pride
Project description:Loss of functional FLCN mutations are known to be the cause of Birt-Hogg-Dubé (BHD) syndrome, in which pulmonary cysts are presented in up to 90% of the patients. Lack of the related disease models in vivo poses a significant barrier to understanding the pathogenic mechanisms, including how the cysts develop and what molecular signaling pathways are involved. In this study, we selectively deleted Flcn specifically in lung mesenchymal cells using a Tbx4-rtTA/TetO-Cre driver. These mice exhibit defective postnatal lung alveolarization. Most strikingly, alveolar enlargement continues into adulthood in these mice, accompanied by bilateral pulmonary cyst formation that resemble human BHD. Interestingly, Flcn deletion in lung epithelial cells alone did not exhibit any alveolar enlargement. No synergistic or additive effects were detected in mouse lungs with combined Flcn deletion in both epithelial and mesenchymal compartments compared to the mice with lung mesenchymal Flcn knockout. We have compared differential gene expression of lung tissues between Flcn knockout in mesenchyme and wild type control mice by RNA-seq.
2025-12-02 | GSE266599 | GEO
Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes. RNA was prepared from pre-reproductive adults in both WTN2 and RB1035 (harboring a flcn-1 mutant allele, mutant worms had been backcrossed wo WTN2 8 times) using biological triplicates. RNA was labeled and hybridized to Agilent C. elegans whole genome microarrays and scanned using a Agilent Technologies Scanner G2505C US22502540.
2012-12-31 | E-GEOD-43207 | biostudies-arrayexpress
Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes.
2012-12-31 | GSE43207 | GEO
Project description:Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
| PRJNA476937 | ENA
Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.
2022-07-11 | PXD025798 | Pride
Project description:Mutations in the Folliculin (FLCN) gene are responsible for the Birt-Hogg-Dube’ (BHD) syndrome, a rare inherited condition that predisposes affected individuals to develop pulmonary cysts, skin and kidney tumors. However, its involvement in liver carcinogenesis has never been investigated so far. Here we demonstrated that FLCN depletion in mice results in sporadic liver cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). Total RNA was extracted from n=4 for each experimantal group: Transcriptomic analysis was performed on males and females at 12- and 90-weeks of age.
2025-03-28 | GSE269752 | GEO