Article

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

University of Adelaide, Tarndarnya, South Australia, 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
    • "The numbering of the mutations given here are based on the deduced amino acid sequence of the human 4-subunit, which differs from that used in the original articles based on the Torpedo sequence and nomenclature system. Additionally three missense mutations of V287L (De Fusco et al., 2000), V287M (Phillips et al., 2001), and I312M (Bertrand et al., 2005) of CHRNB2 have been identified in ADNFLE. Moreover, a heterozygous missense I1287N of CHRNA2 was described in a pedigree where the phenotype of affected individuals was comparable to ADNFLE (Aridon et al., 2006). "
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    ABSTRACT: We generated a transgenic rat strain with a missense mutation in V286L (V286L-TG), in the gene encoding the neuronal nicotinic acetylcholine receptor β2 subunit (CHRNB2) found in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To confirm that V286L-TG rats exhibit seizures similar to those observed in humans, gene expression patterns and behavioral phenotypes were analyzed. In situ hybridization using a V286L Chrnb2-selective probe indicated that the transgene was expressed at higher levels in the cortex, hippocampus, and cerebellum of V286L-TG than wild-type littermates (non-TG). Spontaneous epileptic seizures with ictal discharges in electroencephalograms were detected in 45% of V286L-TG rats and the frequency of seizures was 0.73 times a week. This seizure type is similar to "paroxysmal arousals" that are observed in human ADNFLE. V286L-TG rats displayed nicotine-induced abnormal motor activity including seizures in comparison to non-TGs. Response time following nicotine administration occurred faster in V286L-TG than in non-TG rats. V286L-TG rats demonstrated spontaneous epileptic seizures, which are similar to human ADNFLE, and also showed a higher sensitivity to nicotine administration. Thus, the V286L-TG rat model could be a valuable tool for developing novel mechanism-driven treatment strategies for epilepsy and provide a better understanding of ADNFLE. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Jun 2015 · Neuroscience Research
    • "The numbering of the mutations given here are based on the deduced amino acid sequence of the human 4-subunit, which differs from that used in the original articles based on the Torpedo sequence and nomenclature system. Additionally three missense mutations of V287L (De Fusco et al., 2000), V287M (Phillips et al., 2001), and I312M (Bertrand et al., 2005) of CHRNB2 have been identified in ADNFLE. Moreover, a heterozygous missense I1287N of CHRNA2 was described in a pedigree where the phenotype of affected individuals was comparable to ADNFLE (Aridon et al., 2006). "
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    ABSTRACT: In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regards to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbour of the brca1 gene (NBR1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 effect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.
    No preview · Article · Oct 2014 · Brain Pathology
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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.
    Full-text · Article · Jul 2014 · Frontiers in Neural Circuits
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