Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG

Abstract

Background-Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results-Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I Kr channel HERG (KCNH2). The mutations dramatically increase I Kr , leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to I Kr blockers. Conclusions-We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Pharmacological approach to the treatment of long and short QT syndromes

“…The inactivated state of the channel normally stabilizes the interaction of the channel with most I Kr blockers. Thus, failure of rectification of current due to loss of inactivation of the channel rendered the I Kr blockers in N588K KCNH2 channels largely ineffective (Brugada et al, 2004;Cordeiro et al, 2005;McPate et al, 2006). Consistent with this observation, heterologous expression showed that affinity of mutant channel to open state channel blockers like quinidine was relatively high McPate et al, 2006).…”

“…Similar to LQTS, SQTS is also genetically heterogeneous disease and thus far mutations in five different genes (Table 1) encoding different cardiac ion channels located on chromosome 7, 10, 11, 12 and 17 have been identified, and the corresponding syndromes have been termed SQT1 to SQT5 depending of chronology of discovery (Brugada et al, 2004;Bellocq et al, 2004;Priori et al, 2005;Antzelevitch et al, 2007). Interestingly, four of those genes are the same as those involved in LQTS; however mutations leading to SQTS have the net effect of increasing rather than decreasing depolarizing forces.…”

“…A mutation in KCNH2 was the first reported gene mutation associated with SQTS (Brugada et al, 2004). In contrast to LQT2, mutations in KCNH2 associated with SQT1 is a gain of function mutation leading to an increase in I Kr .…”

“…Attempts to prolong the QT interval using the selective I Kr blocker, d-sotalol, in SQT1 patients met with failure . Heterologous expression studies revealed that the N588K mutation in KCNH2 not only increases I Kr density but also reduces the affinity of the channel to class III antiarrhythmics such as d-sotalol by 20-fold (Brugada et al, 2004). Similarly, the affinity of another selective I Kr blocker, E-4031, was shown to be reduced (McPate et al, 2006).…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…SQTS has been associated with the gain-of-function mutations in 3 distinct potassium channels, KCNH2, KCNQ1 and KCNJ2 , which cause SQT1, SQT2 and SQT3, respectively [111–114]. Nowadays, more evidences indicate the mutations in LTCC are also linked to SQTS.…”