Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 ( hERG ) Mutations and Identifying New Patients

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 8; p. 1144
• Main Authors: Ono, Makoto, Burgess, Don E, Schroder, Elizabeth A, Elayi, Claude S, Anderson, Corey L, January, Craig T, Sun, Bin, Immadisetty, Kalyan, Kekenes-Huskey, Peter M, Delisle, Brian P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.08.2020; MDPI
• Subjects: Amino acids; Cardiac arrhythmia; Cardiomyocytes; Cell surface; Computer applications; Drugs; ERG1 Potassium Channel - chemistry; ERG1 Potassium Channel - genetics; ERG1 Potassium Channel - metabolism; Etiology; Genetic Testing - methods; hERG; Humans; ion channel; KCNH2; Long QT syndrome; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Long QT Syndrome - therapy; Loss of Function Mutation; Missense mutation; Molecular modelling; Mutation; Physiological aspects; Pluripotency; Potassium channels (voltage-gated); Proteins; Quality control; Review; Stem cells; trafficking; United States; KCNH2; hERG; long QT syndrome; ion channel; trafficking
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10081144

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the gene (also known as the human ether-à-go-go-related gene or ). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the -encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which missense variants confer a high-risk for LQT2.