Birt-Hogg-Dube Syndrome Manifesting as Spontaneous Pneumothorax: A Novel Mutation of the Folliculin Gene.
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ABSTRACT:
SUBMITTER: Kim KS
PROVIDER: S-EPMC5628968 | BioStudies | 2017-01-01
REPOSITORIES: biostudies
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Project description:The folliculin gene (FLCN), also known as BHD, is the only known susceptibility gene for Birt-Hogg-Dubé syndrome. BHDS is the autosomal dominant predisposition to the development of follicular hamartomas, lung cysts, spontaneous pneumothorax, and/or kidney neoplasms. To date, 53 unique germline mutations have been reported. FLCN mutation detection rate is 88%. FLCN encodes a predicted 579-amino acid protein, designated folliculin that is highly conserved between humans and homologs in mice, Drosophila, and C. elegans. We developed the first online database detailing all FLCN variants identified in our laboratory and reported in the literature. The FLCN database applies, and assists researchers in applying HGVS nomenclature guidelines. To date, the FCLN database includes 84 variants: 53 unique germline mutations and 31 SNPs. The majority of FLCN germline mutations are predicted to produce a truncated folliculin, resulting in loss of function. The FLCN mutations consist of: 45% (24/53) deletions, 32% (17/53) substitutions (10 putative-splice site, 5 nonsense, and 2 missense), 15% (8/53) duplications, 6% (3/53) insertion/deletions and 2% (1/53) insertions. The database strives to systematically unify current knowledge of FLCN variants and will be useful to geneticists and genetic counselors while also providing a rapid and systematic resource for investigators.
2009-01-01 | S-EPMC3234166 | BioStudies
Project description:Birt-Hogg-Dubé syndrome (BHDS), which is also called Hornstein-Knickenberg syndrome (HKS), is a hereditary autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN, NM_144997). More pulmonary manifestations (pulmonary cysts and recurrent pneumothoraxes) but fewer skin fibrofolliculomas and renal malignancy are found in Asian BHDS patients compared with other BHDS patients. The atypical manifestation can easily lead to a missed or delayed diagnosis. Here, we report a Chinese family with BHDS that presented with primary spontaneous pneumothorax (PSP) and extensive pulmonary cysts in the absence of skin lesions or renal neoplasms. Next-generation sequencing (NGS) was used to sequence the FLCN gene, and Sanger sequencing was carried out on the samples to confirm the presence of these variants. Among the 13 family members, a novel frameshift variant of FLCN (c.912delT/p.E305KfsX18) was identified in seven individuals. This variant has not been reported before. Bioinformatics analysis showed that the novel variant might lead to a premature stop codon after 18 amino acid residues in exon 9, and this may affect the expression level of FLCN. The identification of this novel frameshift variant of FLCN not only further confirms the familial inheritance of BHDS in the proband but also expands the mutational spectrum of the FLCN gene in patients with BHDS.
2020-01-01 | S-EPMC7667195 | BioStudies
Project description:Birt-Hogg-Dubé syndrome (BHDS), caused by germline mutations in the folliculin (FLCN) gene, predisposes individuals to develop fibrofolliculomas, pulmonary cysts, spontaneous pneumothoraces, and kidney cancer. The FLCN mutation detection rate by bidirectional DNA sequencing in the National Cancer Institute BHDS cohort was 88%. To determine if germline FLCN intragenic deletions/duplications were responsible for BHDS in families lacking FLCN sequence alterations, 23 individuals from 15 unrelated families with clinically confirmed BHDS but no sequence variations were analyzed by real-time quantitative PCR (RQ-PCR) using primers for all 14 exons. Multiplex ligation-dependent probe amplification (MLPA) assay and array-based comparative genomic hybridization (aCGH) were utilized to confirm and fine map the rearrangements. Long-range PCR followed by DNA sequencing was used to define the breakpoints. We identified six unique intragenic deletions in nine patients from six different BHDS families including four involving exon 1, one that spanned exons 2-5, and one that encompassed exons 7-14 of FLCN. Four of the six deletion breakpoints were mapped, revealing deletions ranging from 5688 to 9189 bp. In addition, one 1341 bp duplication, which included exons 10 and 11, was identified and mapped. This report confirms that large intragenic FLCN deletions can cause BHDS and documents the first large intragenic FLCN duplication in a BHDS patient. Additionally, we identified a deletion "hot spot" in the 5'-noncoding-exon 1 region that contains the putative FLCN promoter based on a luciferase reporter assay. RQ-PCR, MLPA and aCGH may be used for clinical molecular diagnosis of BHDS in patients who are FLCN mutation-negative by DNA sequencing.
2011-01-01 | S-EPMC3075348 | BioStudies
Project description:Birt-Hogg-Dubé syndrome (BHD) is a human cancer disorder caused by mutations in the tumor suppressor gene Folliculin (FLCN) with unknown biological functions. Here, we show that the Drosophila homolog of FLCN, dFLCN (a.k.a. dBHD) localizes to the nucleolus and physically interacts with the 19S proteasomal ATPase, Rpt4, a nucleolar resident and known regulator of rRNA transcription. Downregulation of dFLCN resulted in an increase in nucleolar volume and upregulation of rRNA synthesis, whereas dFLCN overexpression reduced rRNA transcription and counteracted the effects of Rpt4 on rRNA production by preventing the association of Rpt4 with the rDNA locus. We further show that human FLCN exhibited evolutionarily conserved function and that Rpt4 knockdown inhibits the growth of FLCN-deficient human renal cancer cells in mouse xenografts. Our study suggests that FLCN functions as a tumor suppressor by negatively regulating rRNA synthesis.
2013-01-01 | S-EPMC3526160 | BioStudies
Project description:BACKGROUND:Birt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma. METHODS:The expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts. RESULTS:Cystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424-5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424-5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency. CONCLUSION:The upregulation of miR-424-5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.
2020-01-01 | S-EPMC7279199 | BioStudies
Project description:BACKGROUND:Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by benign growth of the hair follicles, the presence of pulmonary cysts, spontaneous pneumothorax, and bilateral renal tumors that are usually hybrid oncocytic or multifocal chromophobe renal cell carcinoma. The diagnosis is confirmed by the presence of a pathogenic variant in the tumor suppressor folliculin (FLCN) gene mapped at 17p11.2. Although the dermatological lesions typical of BHDS are benign and only cause aesthetic concerns, and the pulmonary manifestations are controllable, the greater tendency of patients with this syndrome to present benign or malignant renal tumors, often bilateral and multifocal, makes the diagnosis of this syndrome important for the prognosis of the patients. The objective was to report the case of a patient with BHDS, without pulmonary manifestations and with hyperplastic polyposis of the gastrointestinal tract, and to perform a literature review. CASE PRESENTATION:A 60-year-old man complained of abdominal pain and diarrhoea for 2?months. Physical examination was normal except for the presence of normochromic papules in the frontal region of the face associated with hyperkeratotic and hyperchromic papules in the dorsal region. The excisional biopsies of the skin lesions indicated trichodiscomas. Esophagogastroduodenoscopy, enteroscopy, and colonoscopy showed the presence of hyperplastic polyps in the stomach, duodenum, jejunum, colon, and rectum. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed multiple expansive solid lesions in both kidneys, with necrotic and calcified areas. Renal magnetic resonance angiography also showed a solid lesion in the right kidney measuring 5?cm in diameter and another solid lesion in the left kidney measuring 8?cm in diameter, both suggestive of renal angiomyolipoma. CT scans of the skull, chest, and temporal bones were normal. The genetic study revealed the presence of a variant of FLCN in the intron 13. CONCLUSIONS:To the best of our knowledge, this is the first reported case of BHDS with the simultaneous finding of gastrointestinal hyperplastic polyposis, which may represent a possible phenotypic expression of this syndrome that has not yet been described.
2020-01-01 | S-EPMC7071710 | BioStudies
Project description:Germline mutations in the folliculin (FLCN) tumor suppressor gene are linked to Birt-Hogg-Dubé (BHD) syndrome, a dominantly inherited genetic disease characterized by predisposition to fibrofolliculomas, lung cysts, and renal cancer. Most BHD-linked FLCN variants include large deletions and splice site aberrations predicted to cause loss of function. The mechanisms by which missense variants and short in-frame deletions in FLCN trigger disease are unknown. Here, we present an integrated computational and experimental study that reveals that the majority of such disease-causing FLCN variants cause loss of function due to proteasomal degradation of the encoded FLCN protein, rather than directly ablating FLCN function. Accordingly, several different single-site FLCN variants are present at strongly reduced levels in cells. In line with our finding that FLCN variants are protein quality control targets, several are also highly insoluble and fail to associate with the FLCN-binding partners FNIP1 and FNIP2. The lack of FLCN binding leads to rapid proteasomal degradation of FNIP1 and FNIP2. Half of the tested FLCN variants are mislocalized in cells, and one variant (?E510) forms perinuclear protein aggregates. A yeast-based stability screen revealed that the deubiquitylating enzyme Ubp15/USP7 and molecular chaperones regulate the turnover of the FLCN variants. Lowering the temperature led to a stabilization of two FLCN missense proteins, and for one (R362C), function was re-established at low temperature. In conclusion, we propose that most BHD-linked FLCN missense variants and small in-frame deletions operate by causing misfolding and degradation of the FLCN protein, and that stabilization and resulting restoration of function may hold therapeutic potential of certain disease-linked variants. Our computational saturation scan encompassing both missense variants and single site deletions in FLCN may allow classification of rare FLCN variants of uncertain clinical significance.
2020-01-01 | S-EPMC7660926 | BioStudies
Project description:Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied.BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets.Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1?-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression.Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1?-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.
2010-01-01 | S-EPMC3012009 | BioStudies
Project description:Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.
2012-01-01 | S-EPMC3418720 | BioStudies
Project description:Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD.We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments.Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8.We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases.
2017-01-01 | S-EPMC5450333 | BioStudies