Cardiac potassium channel dysfunction in sudden infant death syndrome

Abstract

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5–10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I_Kr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I_Ks characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I_Ks incorporated into the Luo–Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

Introduction

Life-threatening arrhythmias including the congenital long QT syndrome (LQTS) have been proposed to contribute to some cases of the sudden infant death syndrome (SIDS), the leading cause of death among infants 1 month to 1 year of age [1], [2], [3]. Supporting this theory are recent observations that mutations in genes responsible for LQTS are found in approximately 5–10% of SIDS cases [4], [5], [6]. Congenital LQTS is an inherited disorder associated with mutations in genes predominantly encoding subunits of cardiac ion channels [7]. The disorder is caused by impaired ventricular repolarization leading to prolongation of the QT interval and an increased risk for life-threatening ventricular arrhythmias. Other mutations in some of the same genes (KCNH2, KCNQ1) can enhance repolarization and cause shortening of the QT interval [8], [9], [10]. In the short QT syndrome (SQTS), there is also increased risk for cardiac arrhythmias and sudden death [11], [12].

Data linking cardiac potassium channel mutations with SIDS include anecdotal reports and population surveys. In 2001, Schwartz and colleagues reported discovery of a de novo KCNQ1 mutation (P117L) in a SIDS victim [13]. The same mutation was also observed to segregate with autosomal dominant LQTS at reduced penetrance in an unrelated Italian family [13]. Another missense KCNQ1 variant (H105L) without functional consequences was discovered among 41 German SIDS cases [14]. Two novel KCNH2 mutations (K101E, P1157L) have also been reported in single SIDS probands [5], [15], and in one case this finding led to discovery of undiagnosed LQTS in family members [15]. But, there have been no studies demonstrating that any of these mutant channels are dysfunctional.

Ackerman et al. reported a systematic survey of autopsied SIDS cases for mutations in the LQTS genes, an effort that originally identified two SCN5A mutations in 93 subjects [4]. The study later reported novel mutations in cardiac potassium channel genes (KCNH2-G294V, KCNQ1-T600M) occurring in two SIDS victims [5]. Three other potassium channel variants were identified, but these alleles were also observed in ethnically matched population controls, albeit rarely. Most recently, the largest series of cases screened for mutations in arrhythmia-susceptibility genes revealed novel missense KCNH2 and KCNQ1 mutations in Norwegian SIDS victims [6]. Importantly, the electrophysiological consequences of these novel SIDS-associated potassium channel mutations were previously unknown.

We report here the functional characterization of novel KCNH2 and KCNQ1 mutations identified in the Norwegian SIDS study. Our findings demonstrated a diversity of functional phenotypes that revealed plausible explanations for sudden death in this clinical setting.