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Splice-Site Mutation Causing Partial Retention of Intron in the FLCN Gene in Birt-Hogg-Dubé Syndrome

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Splice-Site Mutation Causing Partial Retention of Intron in the FLCN Gene in Birt-Hogg-Dubé Syndrome Furuya et al. BMC Medical Genomics (2018) 11:42 https://doi.org/10.1186/s12920-018-0359-5 CASE REPORT Open Access Splice-site mutation causing partial retention of intron in the FLCN gene in Birt- Hogg-Dubé syndrome: a case report Mitsuko Furuya1* , Hironori Kobayashi2, Masaya Baba3, Takaaki Ito4, Reiko Tanaka5 and Yukio Nakatani6 Abstract Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). Nearly 150 pathogenic mutations have been identified in FLCN. The most frequent pattern is a frameshift mutation within a coding exon. In addition, splice-site mutations have been reported, and previous studies have confirmed exon skipping in several cases. However, it is poorly understood whether there are any splice-site mutations that cause translation of intron regions in FLCN. Case presentation: A 59-year-old Japanese patient with multiple pulmonary cysts and pneumothorax was hospitalized due to dyspnea. BHD was suspected and genetic testing was performed. The patient exhibited the splice-site mutation of FLCN in the 5′ end of intron 9 (c.1062 + 1G > A). Total mRNA was extracted from pulmonary cysts, and RT-PCR assessment andsequenceanalysesweredone.Twodistinctbandsweregenerated;onewaswild-typeandtheotherwasalarger- sized mutant. Sequence analysis of the latter transcript revealed the insertion of 130 base pairs of intron 9 from the beginning of the splice-site between exons 9 and 10. Conclusion: To our knowledge, this is the first report of distinct intron insertion using a BHD patient’s diseased tissue- derived mRNA. The present case suggests that a splice-site mutation can lead to exon skipping as well as intron reading mRNA. The splicing process may be dependent in part on whether the donor or acceptor site is affected. Keywords: Birt-Hogg-Dubé syndrome (BHD), Splice-site mutation, Folliculin (FLCN) Background mutant Flcn and heterozygous knockout mice devel- Birt-Hogg-Dubé syndrome (BHD), also called Hornstein- oped renal tumors [9–12]. Further studies using organ- Knickenberg syndrome, is an inherited disorder character- specific Flcn knockout mice demonstrated characteris- ized by skin fibrofolliculomas, multiple pulmonary cysts tic disorders such as polycystic kidney disease, cardiac and kidney cancers [1, 2]. The gene responsible for hypertrophy and alveolar enlargement, indicating that BHD, folliculin (FLCN), is located at 17p11.2. [3], and FLCN function is involved in a wide variety of human its protein product, FLCN, cooperatively interacts with disorders [13–16]. its partners folliculin-interacting proteins 1 (FNIP1) There are nearly 150 known mutation patterns of and FNIP2, playing important roles in organogenesis FLCN [17, 18]. The most frequent type is a frameshift and tissue homeostasis [4–8]. The FLCN complex binds within an exon region. Less frequent types include with AMPK and regulates mammalian target of rapa- nonsense, in-frame deletion, missense, and splice-site mycin (mTOR) [4–8]. The principal role of FLCN in mutations. There are also intragenic deletions and human diseases is tumor suppression. Around 20–30% duplications [19, 20]. According to the literature, of affected family members are reported to develop splice-site mutations have been reported between renal cell carcinomas (RCCs) [2]. Rats carrying a introns 4–13, and there are at least 19 different splice-site mutation patterns [17, 20]. Some of these * Correspondence: [email protected] 1 splice-site mutations are predicted to cause exon skip- Department of Molecular Pathology, Yokohama City University Graduate FLCN School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan ping [21, 22]. Several cases possess truncated Full list of author information is available at the end of the article mRNAs with exon skipping as determined by RT-PCR © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Furuya et al. BMC Medical Genomics (2018) 11:42 Page 2 of 6 [23–25]. Recently, a study of splice-site mutation pneumothorax. Now an ex-smoker, he had previously cases involving the 5′-end of intron 9 (c.1062 + 2 T > smoked 10–12 cigarettes per day for 25 years. He had not G) demonstrated 2 mutants; composed of a short previously experienced a pneumothorax. He did not have band lacking exon 9 and a large band reading an add- fibrous papules on his face or neck. His medical history itional 130 base pairs (bp) of intron 9 [26]. The large was unremarkable except for a benign colon polyp at the band was much fainter than the short one, and inter- age of 58. His two daughters and an uncle on the maternal preted as a cryptic splice-site [26]. It is not com- side had episodes of pneumothoraces (Fig. 1a). His mother pletely understood whether some splice-site mutations had died of cervical cancer, and had had no episode of aberrantly translate intron regions, forming unconven- pneumothorax. Computed tomography showed multiple tional transcriptional products in the affected organs pulmonary cysts (Fig. 1b). Renal tumors were not detect- of BHD patients. In the current study, we described a able. He underwent pulmonary wedge resection via video case of BHD in which FLCN mRNAs had splicing ab- assisted thoracoscopic surgery (VATS). Intrathoracic ob- errations due to translating a part of an intron. servation revealed transparent cysts 3–30 mm in diameter distributed in the pleura (Fig. 2a, left). After VATS, the pa- Case presentation tient has recovered without complication, and has been Clinical course receiving periodic medical check-ups. From the family his- A 59-year-old Japanese man was admitted to Kumamoto tory and radiological and clinical findings, the patient was Saishunso National Hospital for treatment of spontaneous suspected of BHD. a b Fig. 1 Family tree and radiological findings.(a)The patient is indicated by an arrow. Four members including the patient had episodes of pneumothorax, indicated by black. (b) Computed tomography shows multiple pulmonary cysts (indicated by arrows) Furuya et al. BMC Medical Genomics (2018) 11:42 Page 3 of 6 a b c d e Fig. 2 Lung histology and FLCN analysis. (a) Left: The thoracoscopy revealed multiple subpleural cysts (arrows). Right: Histology of the resected lung. Pulmonary cysts preferentially develop along an interlobular septum, and they are partially incorporated within alveoli. Neither fibrosis nor active inflammation was observed. Stars indicate cyst lumens. (b) Direct sequencing of the FLCN gene. The 5′-end of intron 9 was heterozygously mutated to adenine (arrow; c.1062 + 1G > A). A homozygous SNP was also detected (arrowhead; c.1062 + 6C > T). (c) RT-PCR of FLCN mRNA between exons 8–11. Two products were detected; a wild type (WT) and a mutant (Mut). (d) Western blotting of FLCN in the patient’s lung. Normal lung was used for comparison. The FLCN bands of 64 kDa were detected in both lanes. No additional band was observed in the BHD patient’s lung. (e) Sequence analysis of mutant RT-PCR product. Intron 9 (130 bp) retention was detected between exons 9–10 Pathological finding inflammation, which was distinctively different from the The resected lung tissue contained several cystic lesions. histology of emphysematous bullae. Other cystic lung dis- Microscopically, these cysts were incorporated into orders such as lymphangioleiomyomatosis and chronic peripheral alveolar tissue in one region and interstitial obstructive pulmonary disease were also ruled out. The tissue or visceral pleura in another area (Fig. 2a, right). characteristic histological features were consistent with Most of the cysts developed in contact with bronchovas- BHD-associated pulmonary cysts [27, 28]. cular bundles and/or interlobular septa. Flattened pneu- mocytes lined the inner surface of the cysts, and the Mutation and expression analysis lining cells were frequently exfoliated from the wall. The Genetic counseling was performed, and informed con- cyst walls showed neither fibrous reaction nor active sent was obtained from the patient for FLCN genetic Furuya et al. BMC Medical Genomics (2018) 11:42 Page 4 of 6 testing and related molecular studies after approval of the mutation of the present case was located in the other the Institutional Review Board (IRB) of Yokohama City nucleotide (c.1062 + 1G > A), both mutations identically University. Genetic analysis of FLCN identified a single read the first 130 bp of intron 9 and connected with exon nucleotide mutation at the 5′-end of intron 9 (c.1062 + 10. At the break point of intron 9, retention stopped be- 1G > A) (Fig. 2b). The mutation had been reported as fore a guanine-thymine (GT) sequence (data not shown). pathogenic in a previous study [21]. In addition, a single It is plausible that the GT sequence just after the break nucleotide polymorphism (SNP) was detected in the point could have been misunderstood as a donor site. We vicinity of the splice-site mutation (c.1062 + 6C > T). The could not detect exon skipping in the present study, which patient was finally diagnosed with BHD. might owe in part to experimental design. We investigated Previous studies have identified several sites of exon mRNA expression using the patient’slungthatcontained skipping in FLCN mRNAs in patients with BHD [23–25]. cystic lesions, whereas Rossing et al. used mRNA from The mutation in intron 9 (c.1062 + 1G > A) was predicted transfected COS-7 cells. to cause aberrant FLCN mRNA, but had not been investi- A partial intron retention (130 bp) and the following gated.
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