New Mutation in the Birt Hogg Dube Gene

Sempau, Leticia; Ruiz, Itamar R. G.; González-Morán, Alfonso; Susanna, X.; Hansen, Thomas V.O.

doi:10.1016/s1578-2190(10)70686-7

Cited by 3 publications

(4 citation statements)

References 12 publications

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“…A deletion of the noncoding exons 1–3 would eliminate the putative FLCN promoter in the mutant allele, and significantly reduce the gene expression in lung cysts (data not shown), which is consistent with a previous study that tested the FLCN promoter function in vitro [Benhammou et al, ]. The exons 9–14 deletion and the exon 14 deletion have previously been identified in several BHD families, yet the breakpoints were not identified in these cases [Kunogi et al, ; Sempau et al, ]. The two large deletions are predicted to result in the encoding protein truncation.…”

Section: Discussionsupporting

confidence: 86%

“…Patients with FLCN deletions exhibit a high degree of interfamilial clinical variability. Fibrofolliculomas or perifollicular fibromas were seen in all 10 Caucasian families [Sempau et al, ; Benhammou et al, ; Houweling et al, ], whereas five of the nine Chinese families and two Japanese patients presented with isolated PSP [Kunogi et al, ]. 67.5% of the deletion carriers in this study had a history of pneumothorax, which is similar with the frequency of pneumothorax (61%) in PSP patients with FLCN sequence‐mutations in our previous study [Ren et al, ].…”

Section: Discussionsupporting

confidence: 84%

“…So far, including our findings, totally 20 families and two patients in different ethnic populations have been identified harboring 12 unique FLCN intragenic deletions/duplications (Fig. D) [Kunogi et al, ; Sempau et al, ; Benhammou et al, ; Houweling et al, ; Jandaghi et al, 2013]. Patients with FLCN deletions exhibit a high degree of interfamilial clinical variability.…”

Section: Discussionsupporting

confidence: 62%

“…Pathogenic FLCN mutations are frameshift and nonsense mutations that are predicted to result in a premature protein truncation. Large intragenic deletions/duplications have lately been reported in several BHD families from different ethnic populations [Kunogi et al, ; Sempau et al, ; Benhammou et al, ; Houweling et al, ; Jandaghi et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

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FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax

Ding

Zhu

Zou

et al. 2015

American J of Med Genetics Pt A

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Primary spontaneous pneumothorax (PSP) is a significant clinical problem, affecting tens of thousands patients annually. Germline mutations in the FLCN gene have been implicated in etiology of familial PSP (FPSP). Most of the currently identified FLCN mutations are small indels or point mutations that detected by Sanger sequencing. The aim of this study was to determine large FLCN deletions in PSP families that having no FLCN sequence-mutations. Multiplex ligation-dependent probe amplification (MLPA) assays and breakpoint analyses were used to detect and characterize the deletions. Three heterozygous FLCN intragenic deletions were identified in nine unrelated Chinese families including the exons 1-3 deletion in two families, the exons 9-14 deletion in five families and the exon 14 deletion in two families. All deletion breakpoints are located in Alu repeats. A 5.5 Mb disease haplotype shared in the five families with exons 9-14 deletion may date the appearance of this deletion back to approximately 16 generations ago. Evidences for founder effects of the other two deletions were also observed. This report documents the first identification of founder mutations in FLCN, as well as expands mutation spectrum of the gene. Our findings strengthen the view that MLPA analysis for intragenic deletions/duplications, as an important genetic testing complementary to DNA sequencing, should be used for clinical molecular diagnosis in FPSP.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax

Ding

Zhu

Zou

et al. 2015

American J of Med Genetics Pt A

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Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation

et al. 2016

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Pathogenic germline mutations in the folliculin (FLCN) tumor suppressor gene predispose to Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by the development of cutaneous hamartomas (fibrofolliculomas), multiple lung cysts, spontaneous pneumothoraces and renal cell cancer. In this study, we report the identification of 13 variants and three polymorphisms in the FLCN gene in 143 Danish patients or families with suspected BHD syndrome. Functional mini-gene splicing analysis revealed that two intronic variants (c.1062+2T>G and c.1177-5_1177-3del) introduced splicing aberrations. Eleven families exhibited the c.1062+2T>G mutation. Combined single nucleotide polymorphism array-haplotype analysis showed that these families share a 3-Mb genomic fragment containing the FLCN gene, revealing that the c.1062+2T>G mutation is a Danish founder mutation. On the basis of in silico prediction and functional splicing assays, we classify the 16 identified variants in the FLCN gene as follows: nine as pathogenic, one as likely pathogenic, three as likely benign and three as polymorphisms. In conclusion, the study describes the FLCN mutation spectrum in Danish BHD patients, and contributes to a better understanding of BHD syndrome and management of BHD patients.

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Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

2015

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Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk to develop benign, cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumors. Bilateral multifocal renal tumors that develop in BHD syndrome are most frequently hybrid oncocytic tumors and chromophobe renal carcinoma, but may present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome. BHD-associated renal tumors show inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumor suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3/TFEB transcriptional activity, amino acid-dependent mTOR activation through Rag GTPases, TGF-β signaling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumors. Further understanding of the FLCN pathway will hopefully lead to the development of effective forms of therapy for this disease.

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New Mutation in the Birt Hogg Dube Gene

Cited by 3 publications

References 12 publications

FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax

FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax

Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

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