Functional Abnormalities of HERG Mutations in Long QT Syndrome 2 (LQT2)

• 영문명: Functional Abnormalities of HERG Mutations in Long QT Syndrome 2 (LQT2)
• 발행기관: 대한생리학회-대한약리학회
• 저자명: Masayasu HIRAOKA
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제5권 제5호, 367~371쪽, 전체 5쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2001.01.01

영문 초록

The chromosome 7-linked long QT syndrome (LQT2) is caused by mutations in the human ether-a- go-go-related gene (HERG) that encodes the rapidly activating delayed rectifier K⁺ current, I_Kr, in cardiac myocytes. Different types of mutations have been identified in various locations of HERG channel. One of the mechanisms for the loss of normal channel function is due to membrane trafficking of channel protein. The decreased channel function in some deletion mutants appears to be due to loss of coupling with wild type HERG to form the functional channel as the tetramer. Most of missense mutants with few exceptions could interact with wild type HERG to form functional tetramer and caused dominant negative suppression with co-injection with wild type HERG showing variable effects on current amplitude, voltage dependence, and kinetics of activation and inactivation. Two missense mutants at pore regions of HERG found in Japanese LQT2 (A614V and V630L) showed accentuated inward rectification due to a negative shift in steady-state inactivation and fast inactivation. One mutation in S4 region (R534C) produced a negative shift in current activation, indicating the S4 serving as the voltage sensor and accelerated deactivation. The C-terminus mutation, S818L, could not express the current by mutant alone and did not show dominant negative suppression with co-injection of equal amount of wild type cRNA. Co-injection of excess amount of mutant with wild type produced dominant negative suppression with a shift in voltage dependent activation. Therefore, multiple mechanisms are involved in different mutations and functional abnormality in LQT2. Further characterization with the interactions between various mutants in HERG and the regulatory subunits of the channels (MiRP1 and minK) is to be clarified.

키워드

I_Kr current Inward rectification Missense mutation Trafficking defect Dominant negative suppression