利用离子通道结构评估罕见变异的致病性。
Exploiting ion channel structure to assess rare variant pathogenicity.
机构信息
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
出版信息
Heart Rhythm. 2018 Jun;15(6):890-894. doi: 10.1016/j.hrthm.2018.01.021. Epub 2018 Jan 9.
BACKGROUND
A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants.
OBJECTIVE
The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation.
METHODS
We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels.
RESULTS
The structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign.
CONCLUSION
Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.
背景
一名 27 岁女性因长 QT 综合征就诊。在一家诊断实验室，她被发现携带 2 种变异，即 KCNQ1 Val162Met 和 KCNH2 Ser55Leu，且这两种变异都被归类为“致病性”，部分原因是它们与其他已知致病性变异在序列上接近。
目的
本研究旨在使用蛋白质结构、体外功能测定和家族性分离，评估 KCNQ1 和 KCNH2 变异与临床意义之间的关系。
方法
我们使用家系共分离分析、膜片钳体外电生理学和最近发布的这两种通道的冷冻电镜结构的结构分析。
结果
结构分析表明，KCNQ1 Val162Met 朝向远离功能重要区域，而 Ser55Leu 位于对 KCNH2 快速失活至关重要的结构域。临床表型和电生理学研究进一步支持 KCNH2 Ser55Leu 被正确归类为致病性但 KCNQ1 Val162Met 为良性的结论。
结论
序列空间的接近并不总是准确转化为三维空间的接近。新兴的结构方法将为致病性预测增添价值。
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