Genetic variation at a splicing branch point in intron 7 of STK11: a rare variant decreasing its expression in a Chinese family with Peutz-Jeghers syndrome.

IF 2.5 3区 医学 Q3 ONCOLOGY
Xiufang Wang, Yuanyuan Li, Jingqiong Zhang, Chao Liu, Aiping Deng, Juyi Li
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引用次数: 0

Abstract

Background: Peutz-Jeghers syndrome (PJS), a rare dominantly inherited disease, is primarily characterized by hamartomatous polyps and melanotic macules as well as by an increased risk of cancer. The current study aimed to identify the pathogenic gene and pathogenic mechanism of a proband with PJS, thereby offering precise prevention and treatment strategies for PJS.

Methods: A detailed clinical examination was performed of the proband diagnosed with PJS and her family members. In addition, peripheral venous blood was collected from the family members to extract genomic DNA. The pathogenic genes of the proband were identified using whole-exome sequencing, and the candidate pathogenic variants were verified via Sanger sequencing. Meanwhile, co-segregation tests were performed among six family members. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was performed to assess transcript variants in the peripheral blood cells of patients and non-related healthy controls.

Results: Genetic testing revealed a rare splicing variant c.921-1G > C in STK11 in the proband and in her sister and nephew, and the variant co-segregated among the affected family members and nonrelated healthy controls. The proband phenotypically presented with a rare gastric-type adenocarcinoma of the cervix. RT-PCR revealed that the STK11 c.921-1G > C variant could produce two transcripts. Of note, 40 base pairs were deleted in the aberrant transcript between exons 3 and 4, resulting in a frameshift variant and premature termination of the amino acid in exon 6 and ultimately leading to the loss of its functional domain in the STK11 protein. Finally, RT-PCR showed that compared with healthy controls, STK11 mRNA expression level was < 50% in patients.

Conclusion: The present study results indicated that the rare splicing variant c.921-1G > C in intron 7 of STK11 may be a pathogenic variant in patients with PJS. However, this variant (in intron 7) may not produce abnormal transcripts (deletion of 40 base pairs between exons 3 and 4), and PJS may be attributed to the decrease in STK11 expression. Therefore, this study emphasized the importance of genetic counseling, pre-symptomatic monitoring, and early complication management in PJS.

STK11内含子7剪接分支点的基因变异:在一个患有Peutz-Jeghers综合征的中国家庭中,一个罕见的变异降低了STK11的表达。
背景:佩兹-杰格尔斯综合征(Peutz-Jeghers syndrome,PJS)是一种罕见的显性遗传性疾病,主要特征是火腿肠样息肉和黑色素斑以及癌症风险增加。本研究旨在确定一名 PJS 潜在患者的致病基因和致病机制,从而为 PJS 提供精确的预防和治疗策略:方法:对确诊为 PJS 的概率患者及其家庭成员进行了详细的临床检查。此外,还采集了家庭成员的外周静脉血以提取基因组 DNA。通过全外显子组测序确定了该患者的致病基因,并通过桑格测序验证了候选致病变体。同时,对六名家庭成员进行了共分离测试。最后,还进行了反转录聚合酶链反应(RT-PCR),以评估患者和非相关健康对照者外周血细胞中的转录变异:结果:基因检测结果显示,该患者及其姐姐和外甥的 STK11 中存在一个罕见的剪接变体 c.921-1G > C,该变体在受影响的家庭成员和非相关健康对照组中存在共分离现象。该患者的表型为罕见的胃型宫颈腺癌。RT-PCR显示,STK11 c.921-1G > C变异可产生两个转录本。值得注意的是,异常转录本在第3和第4外显子之间删除了40个碱基对,导致第6外显子中的氨基酸出现移帧变异和过早终止,最终导致STK11蛋白中功能域的缺失。最后,RT-PCR 结果显示,与健康对照组相比,STK11 mRNA 的表达水平有所下降:本研究结果表明,STK11内含子7中的罕见剪接变异c.921-1G > C可能是PJS患者的致病变异。然而,该变异(内含子 7)可能不会产生异常转录本(外显子 3 和 4 之间缺失 40 个碱基对),而 PJS 可能是 STK11 表达减少所致。因此,本研究强调了遗传咨询、症状前监测和早期并发症处理对 PJS 的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.70
自引率
15.60%
发文量
362
审稿时长
3 months
期刊介绍: World Journal of Surgical Oncology publishes articles related to surgical oncology and its allied subjects, such as epidemiology, cancer research, biomarkers, prevention, pathology, radiology, cancer treatment, clinical trials, multimodality treatment and molecular biology. Emphasis is placed on original research articles. The journal also publishes significant clinical case reports, as well as balanced and timely reviews on selected topics. Oncology is a multidisciplinary super-speciality of which surgical oncology forms an integral component, especially with solid tumors. Surgical oncologists around the world are involved in research extending from detecting the mechanisms underlying the causation of cancer, to its treatment and prevention. The role of a surgical oncologist extends across the whole continuum of care. With continued developments in diagnosis and treatment, the role of a surgical oncologist is ever-changing. Hence, World Journal of Surgical Oncology aims to keep readers abreast with latest developments that will ultimately influence the work of surgical oncologists.
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