HERG CHANNEL DYSFUNCTION IN HUMAN LONG QT SYNDROME - INTRACELLULAR-TRANSPORT AND FUNCTIONAL DEFECTS

Mutations in HERG are associated with human chromosome 7-linked congen ital long QT (LQT-2) syndrome. We used electrophysiological, biochemic al, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERO channels with the protein r etained in the endoplasmic reticulum. Other mutations (I593R and G628S ) were processed similarly to wild type HERO protein, but these mutati ons did not produce functional channels. In contrast, the T474I mutati on expressed HERO current but with altered gating properties. These fi ndings suggest that the loss of HERG channel function in LQT-2 mutatio ns is caused by multiple mechanisms including abnormal channel process ing, the generation of nonfunctional channels, and altered channel gat ing.