hERG encodes a potassium channel that is of essential importance to normal cardiac electrophysiology and rhythm control. Its biomedical significance is highlighted by its link to both hereditary (locus LQT2) and acquired Long-QT syndromes. Over 600 deleterious mutations (>440 missense) have been reported in hERG. Why the channel is so susceptible to missense mutations is not known. The majority of LQT2 hERG mutations are believed to result in defective assembly and trafficking to the cell surface-presumably due to misfolding of the nascent hERG channel. There is evidence that folding and trafficking of even wild type channels is tenuous. hERG processing is affected by a wide variety of drugs and environmental stresses. Most investigation has logically focused on how amino acid changes affect channel protein processing. Less is known about mRNA-dependent factors in channel processing. Our preliminary studies analyzed the effects of non-coding (or more appropriately termed, extra-coding information) in hERG mRNA that does not alter amino acid sequence. We found that separate and independent regions of hERG mRNA contain information that greatly affects channel translation and trafficking efficiencies-an unusual occurrence. We postulate that a synergy occurs between the inherently fragile biosynthesis of hERG and the LQT2 missense mutations that contribute to the pathogenesis of hereditary LQT2. Investigation of mechanisms underlying mRNA-dependent processing of hERG channels may lead us to reconsider diagnostic and therapeutic approaches to hereditary and acquired arrhythmia syndromes.
The aims of this project are: 1) To determine the specific locale and nature of mRNA elements that affect efficiency of hERG channel translation and trafficking. 2) To determine co- and post-translational mechanisms for mRNA-sequence- specific regulation of hERG channel protein translation and trafficking. 3) To investigate how hERG mRNA- sequence-specific elements impact the pathogenesis of LQT2.
Malfunction of hERG ion channels through mutations or drug interactions is a common cause of heart rhythm disturbances with risk for sudden cardiac death. The hERG channel has unique properties that seem to make it susceptible to malfunction that are not completely understood. We hypothesize that some of these properties come from information hidden within the DNA and RNA that has been unexplored. We propose to explore and understand this information and test whether it contributes to malfunction of the channel and risk for heart rhythm disturbance.