Disruption of Protein Quality Control of Human Ether-a-go-go Related Gene K+ Channel Results in Profound Long QT Syndrome. Heart rhythm Ledford, H. A., Ren, L., Thai, P. N., Park, S., Timofeyev, V., Sirish, P., Xu, W., Emigh, A. M., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Yamoah, E. N., Zhang, X., Chiamvimonvat, N. 2021


BACKGROUND: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previously study of human ether-a-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING Finger Protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown.OBJECTIVE: The purpose of the current study is to test the role of RNF207 on the function of hERG-encoded K+ channel subunits.METHODS AND RESULTS: Here, we demonstrate that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type (WT) subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human pluripotent stem cell-derived cardiomyocytes.CONCLUSIONS: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and, consequently, cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in LQTS patients.

View details for DOI 10.1016/j.hrthm.2021.10.005

View details for PubMedID 34634443