We localized KvLQT1, a principal myocardial potassium channel, in central neurons, and found that mice bearing human LQT1 mutations in this channel display seizures and malignant cardiac arrhythmias. Our study identifies mutation of KCNQ1, a previously unrecognized neuronal potassium channel in brain, as a cause of epilepsy and provides a neurobiological basis for seizures witnessed in humans bearing mutations in this gene. Since these mutations also cause life-threatening cardiac arrhythmias, they are a molecular risk factor for sudden death in epilepsy (SUDEP). The two mouse models with human LQT1 mutations define a candidate excitability-linked mechanism for SUDEP. Mutant KvLQT1 repolarization defects expressed within the forebrain and brainstem autonomic outflow pathway could compromise a direct relay between the epileptic brain and cardiac pacemaking. We observed brief seizures in both mutant knock-in strains and the majority of the events were similar to subtle human partial seizures. In the EEG, cortical discharges were often, but not always followed within two hundred milliseconds by cardiac conduction disturbances. The high incidence of concurrent EEG/ECG events in the presence of either LQT mutation is consistent with an intermittant dysfunctional neurocardiac interplay, presumably under the influence of other extrinsic autonomic or humoral factors modulating brain excitability and cardiac pacemaking that maintain normal function until the onset of profound bradycardia, hypotension, and death following a prolonged seizure.
The presence of KvLQT1 in neurons within mouse vagal brainstem nuclei raises the possibility that this channelopathy may influence cardiorespiratory physiology. Along with parasympathetic slowing of the heart, the vagal nerve also controls motor tone in the upper airway and stimulates neurogenic pulmonary edema, a finding often reported at autopsy of SUDEP cases (4
). It is therefore plausible that excitability defects in these efferent pathways depress respiration, contributing additional vulnerability during the post-ictal period. In our witnessed instance of SUDEP in a T311I/T311I
mouse, there was a loss of brain wave activity and slowed respiration, followed by a progressive lethal bradycardia during the terminal event. This sequence mirrors that of the only reported human SUDEP case with simultaneous intracranial recording (29
These findings establish the crucial role of KCNQ1
in neuronal network synchronization and epileptogenesis. It is a member of the KCNQ
gene family encoding five voltage-gated delayed rectifier K+
channels (KCNQ1-5), four of which (KCNQ2-5) are also expressed in the brain. Interestingly, the hippocampal immunostaining pattern of KvLQT1 overlaps with networks expressing KCNQ2
proteins (Kv7.2 and Kv7.3 respectively), both of which are also linked to epilepsy by a variety of mutations in human and mouse (30
). The KvLQT1 protein is a pore-forming α-subunit of a channel complex that co-assembles with the β-subunit encoded by KCNE1
(MinK), but not any other member of the KCNQ family, forming a channel that generates the slow delayed rectifier potassium current (IKS
) in human cardiac myocytes. Functional effects of the KCNQ1
mutations producing epilepsy in our models have been extensively studied in Xenopus oocytes where they exert dominant-negative suppression of outward potassium currents when co-expressed with wildtype KvLQT1 subunits (18
). The presence and co-assembly of KvLQT1 and MinK in mouse brain () suggests that the protein may modulate neuronal excitability as a KvLQT1/MinK complex as IKS
does in heart.
The molecular consequences of KCNQ1
mutations fall into several categories: impaired channel assembly and trafficking, dysfunctional ion channel gating, altered interaction with second messengers, and inhibition of binding to regulatory proteins. Almost 300 human KCNQ1
mutations have been identified to date and the majority of variants in the pore region or voltage sensor lead to loss of function and LQTS with or without congenital deafness, a few gain of function mutations are associated with familial atrial fibrillation or short QT syndrome (32
). Individuals with truncations and point mutations in the C terminus are either asymptomatic or exhibit borderline QT prolongation and a mild clinical phenotype (34
). The imperfect correlation between channel physiology and the clinical phenotype in different tissues suggests the possibility that not all human KCNQ1
mutations may give rise to an epileptic phenotype, or may do so only on permissive genomic backgrounds.
The difficulty of distinguishing clinically between syncopy and seizure represent a major challenge to the accuracy of genotype to phenotype correlations in LQT/epilepsy patients. Considering that the most common ictal events observed in the mouse LQT1 models were partial seizures lasting less than ten seconds without prominent clonic movements, it is likely that infrequent subclinical seizure activity in humans with KCNQ1
mutations is often undetected. This is consistent with the experience in epilepsy monitoring units where very brief partial, temporal lobe EEG seizures in otherwise healthy individuals may go unnoticed (35
Although the detection of individuals with epilepsy at risk for SUDEP represents a major clinical challenge, the prevalence of occult cardiac arrhythmia in idiopathic epilepsy is understudied and potentially larger than currently assumed. Russell commented in 1906 that “…cardiac arrest does occur in some cases of epilepsy and … may be far commoner than is suspected. If observations were made on the pulse at the onset of fits by those whose work brings them into contact with epileptic patients in considerable numbers, it would soon be established whether such cardiac arrest be of occasional or of frequent occurrence” (5
). Our literature review of the past 30 years yielded over 80 case reports of seizures associated with cardiac arrythmia, and 47% of these were associated with asytole. A recent report on prolonged ambulatory ECG monitoring in a small group of epilepsy patients revealed that 21% had bradycardia associated with seizures, and 3 of 4 of these showed potentially fatal asystole (36
). Our two mouse models recapitulated the association of epilepsy and a spectrum of cardiac arrythmias, including SUDEP, observed repeatedly in clinical settings and will be useful in the search for therapies to prevent SUDEP. Adrenergic β blockade and implantable pacemakers may prove useful for gene-directed prophylaxis (37
). Finally, mutations in other LQT channels and their interacting subunits expressed in the brain may also cause epilepsy with an increased risk of SUDEP. Here, we suggest that the practicing clinician consider the neurocardiological ramifications of idiopathic epilepsies. Comprehensive clinical and genotypic LQT risk profiling in patients with idiopathic seizure disorders, followed by appropriate therapy, may reduce the likelihood of fatal arrhythmia in these individuals.