I_Ks-Related Long QT Syndrome

LQTS type 1 (LQT1), type 5 (LQT5), and type 11 (LQT11) are linked to mutations that cause a reduction in the slowly activating delayed rectifier K⁺ current (I_Ks) in the heart. The α-subunit of the channel responsible for I_Ks (K_v7.1) is encoded by KCNQ1, and K_v7.1 proteins require the presence of their regulatory β-subunit MinK (encoded by KCNE1) to conduct I_Ks. I_Ks is markedly enhanced by β-adrenergic stimulation through phosphorylation of K_v7.1 channels by protein kinase C (PKC), requiring MinK, and protein kinase A (PKA), requiring A-kinase anchoring proteins (AKAPs). As a result, I_Ks enables the physiological response (i.e., abbreviation) of repolarization to fast heart rates during sympathetic nerve activity.¹¹ In 1991, two linkage studies linked a gene locus on chromosome 11 to LQTS in several unrelated families. Five years later, positional cloning techniques established KCNQ1 as the chromosome 11–linked LQT1 gene.² In 1997, targeted mutational analysis of KCNE1 in two families with LQTS identified two missense mutations in KCNE1 (LQT5).¹² LQT1 is now known to account for nearly 40% of all LQTS cases. LQT5 is rare, and mutations in KCNE1 may be responsible for nearly 3% of all LQTS cases.^13–15 In 2007, targeted mutational analysis of the translated exons of AKAP9, encoding the A kinase anchoring protein type 9 (AKAP9; also called Yatiao), identified a missense mutation in a single patient with LQTS (LQT11). So far, only this one mutation in Yatiao has been linked to LQTS.¹⁶

Long QT Syndrome Type 1

To date, more than 300 mutations in KCNQ1 have been linked to LQT1. Most mutations are missense mutations (≈70%), followed by frameshift mutations (≈10%), splice-site mutations (≈10%), nonsense mutations (≈5%), and in-frame deletions or insertions (≈5%).13–15 Novel mutation detection methods have demonstrated large genomic rearrangements (i.e., copy number variants) in KCNQ1, leading to the complete deletion of one or more exons in LQTS patients who were mutation negative after traditional point mutation analyses.¹⁷ This study suggests that the prevalence of copy number variants in LQT1 may be higher than was previously thought. LQT1 mutations in K_v7.1 are mostly located in the transmembrane segments (≈60%), the intracellular C-terminus (≈30%), and the intracellular N-terminus (≈10%).^13–15 A fraction of these mutations have been investigated in experimental settings, and these studies have revealed an array of molecular mechanisms that underlie I_Ks loss-of-function (Figure 51-1) including (1) defective K_v7.1 protein synthesis, (2) defective trafficking of mutated K_v7.1 proteins to the sarcolemma and their retention in the endoplasmic reticulum, (3) impaired ability of mutated proteins to coassemble into tetrameric channels, (4) altered biophysical properties, (5) disrupted interaction with regulatory proteins, and (6) defective endosomal recycling.^3,18–20 Of note, these mechanisms are not mutually exclusive. Loss-of-function alterations in biophysical properties of mutated I_Ks channels involve a slower rate of channel activation, a shift in the voltage dependence of activation toward more depolarized membrane potentials (indicating later channel activation), and accelerated deactivation (indicating faster channel closing). Disrupted interaction of mutated K_v7.1 proteins with the key regulatory protein AKAP9 has been demonstrated to reduce K_v7.1 phosphorylation by PKA upon β-adrenergic stimulation.¹⁹ Disrupted interaction with phosphatidylinositol-4,5-bisphosphate (PIP2) results in reduced PKC-mediated phosphorylation of the K_v7.1 proteins. PIP2, a sarcolemmal lipid, increases I_Ks activity through phosphorylation.²⁰ I_Ks is also increased by the stress hormone cortisol through the action of the serum- and glucocorticoid-inducible kinase 1 (SGK1). Cortisol upregulates SGK1, thereby facilitating endosomal recycling of K_v7.1 channels and stimulating their insertion into the sarcolemma. Mutations in K_v7.1 can disturb this process, causing further I_Ks reduction upon stimulation of SGK1 by cortisol.¹⁸

Consistent with the molecular signaling pathways, LQT1-related cardiac events occur often during exercise (in particular swimming) and psychological stress, when the adrenergic tone and plasma levels of cortisol are increased.²¹ In addition, the QT interval fails to shorten appropriately, and might even lengthen (paradoxical QT response), in LQT1 patients upon an increase in heart rate (immediately at standing from supine position or at peak exercise, and during the recovery phase of treadmill exercise testing).^22,23 In healthy subjects, QT intervals shorten at faster heart rates, enabling QTc to remain within normal limits with decreasing R-R intervals. Moreover, QTc duration lengthening is also observed in LQT1 patients in response to the intravenous infusion of epinephrine.²⁴ These clinical features indicate loss of an adequate compensatory response of I_Ks to β-adrenergic stimulation and stress hormones, most probably as the result of reduced phosphorylation and disrupted endosomal recycling of mutated K_v7.1 channels. As expected, antiadrenergic therapies such as β-blockers and left stellate ganglion ablation have great efficacy in LQT1 patients.^25,26 β-Blockers have been shown to diminish QTc changes during exercise or standing and significantly reduce the rate of cardiac events.^22,25

Molecular genetics may be useful not only for diagnostic purposes, but also for risk stratification in LQT1. In a multicenter study in 600 LQT1 patients, significantly higher rates of cardiac events were found in patients with mutations located in transmembrane segments or with mutations that exert dominant-negative effects on normal I_Ks channel subunits.⁷ Another large multicenter study associated mutations in highly conserved amino acid residues in K_v7.1 with significant risk of cardiac events.²⁷ Moreover, a recent study in 387 LQT1 patients correlated clinical phenotype with changes in biophysical properties of K_v7.1 channels caused by different KCNQ1 mutations. Especially, a slower rate of channel activation was associated with increased risk for events in LQT1.²⁸ In all these studies, the effects of the mutations were independent of traditional risk factors (i.e., QTc, female gender, and β-blocker therapy). Mutation type and location may be used to predict whether a KCNQ1 mutation is pathogenic or is an innocuous rare variant.²⁹ This is clinically relevant in that large overlap of QTc values has been noted between patients with LQTS and healthy patients. Non-missense mutations, regardless of location, have an estimated predictive value of more than 99% to be pathogenic, and missense mutations have a high predictive value when located in the transmembrane segments, the pore loop, and the C-terminus of K_v7.1 proteins.²⁹ LQT1 patients with a mutation in the cytoplasmic loops are at higher risk for lethal arrhythmias than are patients with a mutation in other regions of K_v7.1, probably because of a pronounced reduction in channel activation upon β-adrenergic stimulation.³⁰

Recent studies have identified single-nucleotide polymorphisms (SNPs) in the nitric oxide 1 adaptor protein gene (NOS1AP) as strong modulators of QT interval duration and risk of cardiac events in LQT1 (and other LQTS types).31,32 First, genome-wide association studies associated SNPs in NOS1AP with QT interval in the general population. Next, a role for NOS1AP SNPs was found in sudden cardiac death in the general population.^33,34 In 2009, a family-based association analysis linked SNPs in NOS1AP with QT interval prolongation and risk for cardiac arrest and sudden death in a large South African cohort of LQT1 patients with the A341V mutation.³¹ NOS1AP encodes CAPON, an accessory protein of the neural nitric oxide synthase, which controls intracellular nitric oxide production. Functional studies indicate that CAPON fastens cardiac repolarization through inhibition of L-type Ca²⁺ channels.³⁵ This provides a rationale for the association of SNPs in NOS1AP with QT interval duration. SNPs in the 3′-untranslated region (3′UTR) of KCNQ1 may also modulate phenotype severity in LQT. In a recent study in two independent LQT1 cohorts from the Netherlands and the United States, SNPs in KCNQ1‘s 3′UTR were associated with QTc duration and symptoms in an allele-specific manner. Patients with derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while patients with these variants on their normal KCNQ1 allele had longer QTc and a greater number of symptoms. Experimental studies showed that the expression of KCNQ1‘s 3′UTR with derived SNP variants was less than the expression of 3′UTR with ancestral SNP variants. The 3′UTR play a crucial regulatory role in gene expression by controlling stability and translation of mRNAs. SNPs in this region were suggested to affect this function of the 3′UTR, thereby altering gene expression in an allele-specific manner.³⁶ If true, this is expected to be especially relevant when one allele contains a pathogenic mutation. However, these findings await replication in larger LQT1 cohorts before their clinical use is proposed.

Long QT Syndrome Type 5

The KCNE-encoded MinK exerts its regulatory effects on K_v7.1 via interactions between the transmembrane segments and the C-termini of the two proteins. In general, interactions between transmembrane segments are believed to be essential for normal channel activation, while interactions between the C-termini regulate channel assembly and channel deactivation. LQT5 mutations involve mainly missense mutations, although in-frame deletions, nonsense mutations, and frameshift mutations are also found.13–15 Most mutations impair the ability of MinK to modulate gating properties of K_v7.1, causing a shift in the voltage dependence of activation toward more depolarized potentials (in particular, mutations in the transmembrane segments) and accelerating deactivation.³⁷ Other mechanisms include defective trafficking of mutated MinK proteins (and thereby K_v7.1 proteins), impaired channel assembly, and reduced sensitivity to PIP2.^20,37 Residues in the C-terminus of MinK are identified as key determinants for sensitivity of K_v7.1 to PIP2, and LQT5-linked mutations in these residues are shown to reduce PIP2-mediated phosphorylation of Kv7.1 proteins by PKC.²⁰ Because of its low prevalence, genotype-phenotype correlations in LQT5 are not available but may resemble those observed in LQT1.

An SNP in KCNE2, D85N, located in the C-terminus of MinK, has been associated with QT interval duration in the general population,33,34 and is shown to be more prevalent in (genotype-negative) LQTS patients.³⁸ Heterologous expression studies revealed significant loss-of-function effects of D85N on KCNQ1-encoded and KCNH2-encoded currents.³⁸ Therefore, D85N is suggested to be a disease-causing variant in LQTS, and certainly a modifier of phenotype in LQT1 and LQT2 patients.

Long QT Syndrome Type 11

AKAP9 (Yatiao) has an N-terminal and a C-terminal binding domain that interacts with the C-terminus of K_v7.1. The only LQT11 mutation described so far (S1570L) has been found in 1 out of 50 genotype-negative unrelated LQTS patients. S1570L is located in the C-terminal binding domain of AKAP9. It has been shown to disrupt, but not eliminate, the interaction between AKAP9 and K_v7.1, leading to reduced cyclic adenosine monophosphate (cAMP)-mediated phosphorylation of K_v7.1 by PKA during β-adrenergic stimulation. This is speculated to result in less I_Ks enhancement during sympathetic nerve activity.¹⁶

Jervell and Lange-Nielsen Syndrome

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