Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis

• 成果类型: Article
• 署名作者: Brewer, Kathryn R.; Vanoye, Carlos G.; Huang, Hui; Moster, Katherine R. Clowes; Desai, Reshma R.; Hayes, James B.; Burnette, Dylan T.; George, Alfred L.; Sanders, Charles R.
• 署名单位: Vanderbilt University; Vanderbilt University; Northwestern University; Feinberg School of Medicine; Vanderbilt University; Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14092
• DOI: 10.1073/pnas.2412971122
• 发表日期: 2025-02-25
• 关键词: prediction

摘要

Loss- of- function (LOF) pathogenic variants in KCNQ1 encoding a cardiac potassium channel predispose to sudden cardiac death in type 1 congenital long QT syndrome (LQT1). To determine the spectrum of molecular mechanisms responsible for this life- threatening condition, we used an integrative approach to determine the biophysical, functional, and trafficking properties of 61 KCNQ1 variants distributed throughout all domains of the channel. Impaired trafficking to the plasma membrane was the most common cause of LOF across all channel domains, often but not always coinciding with protein instability. However, many LOF variants, particularly in transmembrane domains, trafficked normally, but when coexpressed with KCNE1 exhibited impaired conductance, altered voltage dependence, or abnormal gating kinetics, highlighting diverse pathogenic mechanisms. This indicates a need for personalized treatment approaches for LQT1. Use of our data to benchmark variant pathogenicity prediction methods demonstrated that prediction accuracy depends on the exact mechanism of pathogenicity associated with a given variant.