The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits

Department of Neurosciences, Medical Faculty, CMU, 1211 Geneva 4, Switzerland.
Neurobiology of Disease (Impact Factor: 5.08). 01/2006; 20(3):799-804. DOI: 10.1016/j.nbd.2005.05.013
Source: PubMed


Mutations in nAChRs are found in a rare form of nocturnal frontal lobe epilepsy (ADNFLE). Previously, some nAChR mutations have been described that are associated with additional neurological features such as psychiatric disorders or cognitive defects. Here, we report a new CHRNB2 mutation located in transmembrane region 3 (M3), outside the known ADNFLE mutation cluster. The CHRNB2 mutation I312M, which occurred de novo in twins, markedly increases the receptor's sensitivity to acetylcholine. Phenotypically, the mutation is associated not only with typical ADNFLE, but also with distinct deficits in memory. The cognitive problems are most obvious in tasks requiring the organization and storage of verbal information.

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    • "Interest for nAChR in several epileptic syndromes previously considered “idiopathic” was rekindled by the finding that altered functional properties of nAChR are implicated in the pathogenesis of nocturnal frontal lobe epilepsy (NFLE), and that seizures induced by nicotine in rodents model nAChR-related epilepsy. NFLE is linked with mutations of the α4 or β2 subunits [2], [3], [4], [5], [6], [7], the most abundantly expressed subunits in the CNS [8]. Though in human NFLE, or in genetically engineered mice that model the disease, functional properties of nAChRs are intimately altered, nicotine evokes seizures by over-activating a healthy system. "
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
    PLoS ONE 05/2013; 8(5):e64541. DOI:10.1371/journal.pone.0064541 · 3.23 Impact Factor
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    • "Mutations in the CHRNA4, CHRNB2, and CHRNA2 genes respectively encoding the α4, β2, and α2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR) have been reported in less than a quarter of families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [4]. Mutations in CHRNA4 and CHRNB2 have been found even in sporadic cases [6] [7] [8] [9] [10] [11] [12]. "
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    ABSTRACT: The beneficial effect of nicotine has been reported in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) patients, but not tested in sporadic cases. Recently, a nicotine defect in the arousal pathway has been hypothesized even in sporadic NFLE patients and their relatives. This case-control family study was designed to test whether NFLE subjects were more likely to use tobacco than controls, as an indirect marker of cholinergic arousal system dysregulation. At least four relatives were included for each NFLE proband and control. Each subject was questioned about tobacco habits; 434 individuals were recruited. Moreover, we compared NFLE patients with age- and sex-matched controls to determine whether they are more likely to use tobacco. We found a slightly higher trend of tobacco use in NFLE probands compared to that in control subjects; we did not find any significant difference in the distribution of tobacco use among NFLE group compared to that in the control group.
    Epilepsy & Behavior 12/2012; 26(1). DOI:10.1016/j.yebeh.2012.10.014 · 2.26 Impact Factor
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    • "Subsequently, mutations in genes coding for the alpha2 and beta2 subunits of the acetylcholine receptor (CHRNA2 and CHRNB2) were identified [31], confirming a heterogeneous genetic condition [28]. At present only two de novo mutations in these genes have been reported [32] [33]. Further linkage analysis in ADNFLE families without known mutations revealed three additional loci on chromosomes 15q24 [34], 3p22-24, and 8q11.2-q21.1 [35], but causative mutations have not yet been found. "
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    ABSTRACT: Nocturnal frontal lobe epilepsy (NFLE) is characterized by seizures with complex, often bizarre, violent behaviour arising only or mainly during sleep. These unusual seizures and their occurrence during sleep are often accompanied by normal EEG tracings and neuroradiological findings, making it difficult to distinguish NFLE seizures from other non-epileptic nocturnal paroxysmal events, namely parasomnias. NFLE was described for the first time in 1981, but, as its epileptic origin was controversial, the condition was called nocturnal paroxysmal dystonia. Even though many aspects of parasomnias and NFLE have been clarified in the last two decades, the problem of differential diagnosis remains a challenge for clinicians. This paper discusses some controversial points still under debate. The difficulties in distinguishing nocturnal epileptic seizures from parasomnias reflect just one aspect of the intriguing issue of the pathophysiological relationships between all types of paroxysmal motor behaviours during sleep.
    Sleep Medicine 12/2011; 12 Suppl 2(Suppl 2):S27-32. DOI:10.1016/j.sleep.2011.10.008 · 3.15 Impact Factor
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