Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

Abstract

Background Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in diabetics. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia susceptibility genes - including the KCNE2 K+ channel β subunit - are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Methods and Results Using “whole transcript” transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2−/− mouse pups, and adrenal remodeling consistent with metabolic syndrome in adult Kcne2−/− mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes, hypercholesterolemia, hyperkalemia, anemia and elevated angiotensin II. Kcne2 deletion was also prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately following transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia and atrioventricular block. Conclusions Disruption of a single, widely expressed arrhythmia susceptibility gene can generate a multisystem syndrome comprising manifold electrical and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology

“…It is likely, as with Long QT syndrome, that given enough time and patients, KCNE2 polymorphisms associated with at least subclinical hypochlorhydria will emerge, and possibly rarely associate with familial gastric cancer particularly if homozygous recessive cases of KCNE2 loss-of-function mutations occur (as is observed for hearing loss in LQTS patients with KCNE1 mutations and Jervell and Lange-Nielsen syndrome). We also discovered, unsurprisingly because low gastric pH is required for efficient iron absorption, that Kcne2 −/− mice exhibit iron-deficiency anemia 47 , a finding later confirmed by others 51 . Again, it will be of interest to see whether human KCNE2 polymorphisms, as with KCNQ1, correlate with anemia.…”

“…This probably reflects both the loss in constitutive activation and the protection from inhibition by extracellular low pH that KCNE2 provides. While there may be other, non pH-related mechanisms for the more severe gastric hyperplasia in Kcne2 −/− Kcne3 −/− mice compared to Kcne2 −/− mice, we suggest that basolateral KCNQ1-KCNE3 channels in Kcne2 −/− mice, while not able to return K + directly to the stomach, can facilitate K + exit from parietal cells into the bloodstream, partly mitigating the loss of downhill K + gradient from stomach lumen to parietal cell 47 . This may explain the slightly less severe loss of gastric acidification in Kcne2 +/− Kcne3 −/− mice compared to Kcne2 +/− Kcne3 +/+ mice.…”

“…In a more recent study, we recapitulated the lack of effect of Kcne2 deletion on baseline QTc at 4 months, but found that in older mice (7 months) Kcne2 deletion did cause QTc prolongation 47 . Monogenic cardiac arrhythmia syndromes are typically considered solely from the perspective of direct disruption of cardiac myocyte ion currents generated by channel complexes containing the mutated gene.…”

“…In a single colony of C57BL/6 laboratory mice, which is genetically more homogeneous than a typical human population, and in which environment and nutrition can be controlled, and age- and sex-matched littermates directly compared, Kcne2 deletion causes a battery of extracardiac consequences that can impact cardiac structure and function 47 . First, as described above, Kcne2 deletion causes hypothyroidism most prominently in pups from Kcne2 −/− dams and this alters cardiac structure and impairs contractility 52 .…”

Novel exon 1 protein‐coding regions N‐terminally extend human KCNE3 and KCNE4

“…KCNE proteins are so widely studied because they can exert sometimes dramatic effects on Kv channel function (5)(6)(7)(8)(9)(10)(11), are obligate partners for many Kv a subunits in vivo (5,6,(9)(10)(11)(12)(13)(14)(15)(16)(17), can alter Kv channel pharmacology with respect to clinically relevant and investigational drugs (18,19), and their reach is impressive, each modulating multiple Kv a subunits and, in some cases, other channel types (20,21). In addition, sequence variants in each of the 5 human (h)KCNE genes are associated with one or more forms of potentially lethal cardiac arrhythmia (22)(23)(24)(25)(26)(27)(28)(29)(30) [for recent review, see Crump et al (31)], and Kcne-knockout mice exhibit a wide range of sometimes dramatic phenotypes (12)(13)(14)(15)(16)(17)(32)(33)(34), which suggests that additional discoveries of hKCNElinked diseases in other tissues will follow.…”