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首页> 外文期刊>BMC Medical Genetics >Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer
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Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

机译：与肾脏癌相关的肿瘤抑制基因FLCN的剪接位点突变

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Background Renal 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. Methods Using 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. Results Here 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. Conclusions Identification 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.
机译：背景肾细胞癌是最普遍的恶性肿瘤之一。通常是零星的。然而，对罕见的家族形式的遗传研究已导致鉴定致病基因（例如VHL和FLCN）中的突变。 FLCN基因中的突变是Birt-Hogg-Dubé综合征的病因，Birt-Hogg-Dubé综合征是一种罕见的肿瘤综合征，其特征在于肾细胞癌，气胸和皮肤肿瘤的结合。方法采用Sanger测序技术，我们在患有肾细胞癌的患者的淋巴细胞DNA中鉴定了FLCN中杂合的剪接位点突变。此外，针对该突变分析了肿瘤DNA和来自转移的DNA。序列改变的致病作用已通过小基因检测得以证实，并使用TALEN介导的转基因作用在培养细胞中检测了对蛋白质的生化后果。结果在这里，我们描述了一名55岁患者的FLCN突变，该患者表现为进行性体重减轻，双侧肾囊肿和肾肿瘤。在过去的几十年中，他和家人都有气胸复发的病史。肿瘤肾切除术后的组织学显示混合性肾癌由发色团肾细胞癌和去分化的小细胞癌成分组成。随后的FLCN测序鉴定了一个内含子c.1177-5_-3delCTC改变，最有可能影响FLCN基因外显子11的正确剪接。我们证明了外显子11的跳过是该突变的结果，该突变导致阅读框中的移位和过早终止密码子的插入。有趣的是，截短的蛋白尽管在细胞培养和肿瘤组织中都非常不稳定，并且其亚细胞定位与野生型FLCN不同，但仍可以表达。通过阻止蛋白酶体和溶酶体降解，可以部分逆转改变的蛋白质稳定性和亚细胞定位。结论识别BHD综合征致病突变需要分析内含子序列。然而，在这些情况下，对所得蛋白质进行连续改变的生化验证尤为重要。 BHD综合征中致病突变的功能表征可能为进一步开发新的诊断和治疗策略提供指导。

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