Pneumothorax Developing for the First Time in a 73-year-old Woman Diagnosed with Birt-Hogg-Dubé Syndrome

Okura, Makiko; Yae, Toshifumi; Nagashima, Osamu; Hirai, Shu; Kumasaka, Takashi; Iwase, Akihiko

doi:10.2169/internalmedicine.52.0338

Cited by 10 publications

(3 citation statements)

References 8 publications

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“…The mutation detected in our patient had been found in patients fulfilling at least a subset of clinical features of BHD syndrome before [ 23 , 24 ]. However, whether the intronic variant observed really leads to a change in the resulting protein had not been proven on a biochemical level.…”

Section: Discussionmentioning

confidence: 87%

“…Since the mutation had been reported before in association with the clinical diagnosis of BHD syndrome [ 4 , 23 , 24 ] and the family in the latter report only presented with asymptomatic pneumothorax respectively lung cysts and skin manifestation we decided to further evaluate the effect of this sequence alteration to confirm its pathogenic potential on a molecular level. To validate the mutation’s impact on splicing of the FLCN transcript we generated minigene constructs containing either the FLCN wild-type (WT) or the c.1177-5—3 del CTC (Mut) sequence.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

et al. 2017

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BackgroundRenal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors.MethodsUsing Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells.ResultsHere we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation.ConclusionsIdentification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0416-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

et al. 2017

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“…These three symptoms appear separately [1, 2]. Lung-related symptoms are often the earliest phenotypical manifestations to appear, but most patients are asymptomatic [3, 4]. The pulmonary manifestations of BHD occasionally need to be distinguished from other conditions associated with diffuse cysts lung diseases (DCLD), such as lymphangioleiomyomatosis, Langerhans cell histiocytosis, lymphocytic interstitial and pneumonitis [5].…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome

Liu

Feng

et al. 2017

Orphanet J Rare Dis

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BackgroundBirt-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.MethodsWe 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.Main resultsAmong 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0656-7) contains supplementary material, which is available to authorized users.

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Pleural Disease in Diffuse Cystic Lung Diseases

Seyama

Kurihara

2021

Diffuse Cystic Lung Diseases

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Pneumothorax Developing for the First Time in a 73-year-old Woman Diagnosed with Birt-Hogg-Dubé Syndrome

Cited by 10 publications

References 8 publications

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome

Pleural Disease in Diffuse Cystic Lung Diseases

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