CHRNB2 Is the Second Acetylcholine Receptor Subunit Associated with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy*

Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2001; 68(1):225-31. DOI: 10.1086/316946
Source: PubMed

ABSTRACT Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.

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Available from: David Robert Goudie, Apr 12, 2014
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    • "However, as in many other epilepsies, approximately 30% of the patients remain unresponsive to therapy (Picard and Brodtkorb, 2008). About 10–12% of the ADNFLE families bear mutations on genes coding for nicotinic acetylcholine receptors (nAChR) subunits (Steinlein et al., 1995; De Fusco et al., 2000; Phillips et al., 2001; Aridon et al., 2006). Another gene recently "
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    ABSTRACT: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial sleep-related epilepsy which can be caused by mutant neuronal nicotinic acetylcholine receptors (nAChR). We applied multi-electrode array (MEA) recording methods to study the spontaneous firing activity of neocortical cultures obtained from mice expressing or not (WT) an ADNFLE-linked nAChR subunit (β2-V287L). More than 100,000 up-states were recorded during experiments sampling from several thousand neurons. Data were analyzed by using a fast sliding-window procedure which computes histograms of the up-state durations. Differently from the WT, cultures expressing β2-V287L displayed long (10-32 s) synaptic-induced up-state firing events. The occurrence of such long up-states was prevented by both negative (gabazine, penicillin G) and positive (benzodiazepines) modulators of GABAA receptors. Carbamazepine (CBZ), a drug of choice in ADNFLE patients, also inhibited the long up-states at micromolar concentrations. In cultures expressing β2-V287L, no significant effect was observed on the action potential waveform either in the absence or in the presence of pharmacological treatment. Our results show that some aspects of the spontaneous hyperexcitability displayed by a murine model of a human channelopathy can be reproduced in neuronal cultures. In particular, our cultures represent an in vitro chronic model of spontaneous epileptiform activity, i.e., not requiring pre-treatment with convulsants. This opens the way to the study in vitro of the role of β2-V287L on synaptic formation. Moreover, our neocortical cultures on MEA platforms allow to determine the effects of prolonged pharmacological treatment on spontaneous network hyperexcitability (which is impossible in the short-living brain slices). Methods such as the one we illustrate in the present paper should also considerably facilitate the preliminary screening of antiepileptic drugs (AEDs), thereby reducing the number of in vivo experiments.
    Frontiers in Neural Circuits 07/2014; 8:87. DOI:10.3389/fncir.2014.00087 · 3.60 Impact Factor
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    • "Among them, genes encoding neuronal nicotinic acetylcholine receptor (nAChR) subunits have emerged as candidate genes for inherited idiopathic epilepsies. Mutations of the genes coding for the nAChR a4 (CHRNA4), a2 (CHRNA2), and b2 (CHRNB2) subunits are associated with autosomal dominant nocturnal frontal lobe epilepsy (Phillips et al., 2001; Rozycka et al., 2003; Hoda et al., 2009). Chromosomal regions harboring genes encoding subunits of the nAChRs were also screened for linkage to JME and the tested variants of CHRNA4 conferred genetic susceptibility to this epileptic syndrome (Rozycka et al., 2009). "
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    ABSTRACT: There is evidence of linkage between the 15q13–q14 locus, containing the gene encoding the a7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) and its partially duplicated isoform (CHRFAM7A), and epilepsy. Additionally, a 2-bp deletion polymorphism (c.497–498delTG; rs67158670) in CHRFAM7A, resulting in a frame shift and truncation of the protein product, is associated with some neuro-logical diseases. This study was designed to explore the possibility of an association of the c.497–498delTG polymorphism of CHRFAM7A with idiopathic generalized epilepsies (IGEs) in Polish children and young pa-tients. The study included 197 IGE patients and 258 unrelated healthy individuals. The frequency of the CHRFAM7A c.497–498delTG polymorphism was determined in each group using heteroduplex analysis. An association between the c.497–498delTG polymorphism of CHRFAM7A and IGE was evidenced. It was dem-onstrated that the frequency of the CHRFAM7A 2-bp deletion carriers was significantly lower in the IGE patients than in the control group. The observed frequency of 2-bp deletion carriers was high in IGE subjects (64%), but significantly higher in control subjects (76%). Carriers of at least one copy of the -2 bp allele had halved their risk of IGE susceptibility (delTG/delTG and delTG/wild-type versus wild-type/wild-type: odds ratio = 0.55; 95% confidence intervals = 0.365–0.827; p = 0.004). Moreover, it has been demonstrated that this polymorphic variant is associated with the c.524-12_524-11insGTT variation (rs10649395) in intron 7 of CHRFAM7A. Our study substantiates the involvement of the a7 subunit of nAChR in the pathophysiology of IGEs and indicates that the CHRFAM7A c.497–498TG deletion or a nearby polymorphism may play a role in the pathogenesis of IGE. Further work should concentrate on ascertaining the exact mechanism of this polymorphism's effect and its relationship with IGE.
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    • "Heteromeric nAChRs are thought to give a major contribution to such sustained control of neocortical excitability, as they display higher sensitivity to the agonists and slower desensitization, compared with the homomeric forms. Consistently, the large majority of mutations known to be linked to autosomal dominant nocturnal frontal lobe epilepsy and affine pathologies map on genes coding for non-a7 nAChR subunits (Aridon et al., 2006; Becchetti, 2012; De Fusco et al., 2000; Phillips et al., 2001; Steinlein et al., 1995). Control of neocortical excitability depends on a fine balance between excitatory and inhibitory transmission , and nAChRs are known to regulate both. "
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    ABSTRACT: We studied how nicotinic acetylcholine receptors (nAChRs) regulate glutamate release in the secondary motor area (Fr2) of the dorsomedial murine prefrontal cortex, in the presence of steady agonist levels. Fr2 mediates response to behavioral situations that require immediate attention and is a candidate for generating seizures in the frontal epilepsies caused by mutant nAChRs. Morphological analysis showed a peculiar chemoarchitecture and laminar distribution of pyramidal cells and interneurons. Tonic application of 5 μM nicotine on layer V pyramidal neurons strongly increased the frequency of spontaneous glutamatergic excitatory postsynaptic currents (EPSCs). The effect was inhibited by 1 μM dihydro-β-erythroidine (DHβE, which blocks α4-containing nAChRs), but not by 10 nM methyllicaconitine (MLA, which blocks α7-containing receptors). EPSCs were also stimulated by 5-iodo-3-[2(S)-azetidinylmethoxy]pyridine (5IA85380), selective for β2-containing receptors, in a DHβE-sensitive way. We next studied the association of α4 with different populations of glutamatergic terminals, by using as markers the vesicular glutamate transporter type 1 (VGLUT1) for cortico-cortical synapses, and type 2 (VGLUT2) for thalamo-cortical projecting fibers. Immunoblots showed higher expression of α4 in Fr2, as compared to the somatosensory (SS) cortex. Immunofluorescence showed intense VGLUT1 staining throughout the cortical layers, whereas VGLUT2 immunoreactivity displayed a more distinct laminar distribution. In layer V, co-localization of α4 nAChR subunit with both VGLUT1 and VGLUT2 was considerably stronger in Fr2 than in SS cortex. Thus, in Fr2, α4β2 nAChRs are expressed in both intrinsic and extrinsic glutamatergic terminals and give a major contribution to control glutamate release in layer V, in the presence of tonic agonist levels. Synapse, 2013. © 2013 Wiley Periodicals, Inc.
    Synapse 06/2013; 67(6). DOI:10.1002/syn.21655 · 2.13 Impact Factor
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