An Insertion Mutation of the CHRNA4 Gene in a Family With Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Steinlein, Ortrud K.; Magnússon, Andrés; Stoodt, Jens; Bertrand, Sonia; Weiland, Sigrid; Berkovic, Samuel F.; Nakken, Karl Otto; Propping, Peter; Bertrand, Daniel

doi:10.1093/hmg/6.6.943

Cited by 339 publications

(242 citation statements)

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“…The α4 subunit mutation S248F was identified in this family and was the first known human epilepsy mutation (69). A second α4 mutation was later found in a Norwegian family (68).…”

Section: Ligand-gated Acetylcholine Receptorsmentioning

confidence: 69%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

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“…The α4 subunit mutation S248F was identified in this family and was the first known human epilepsy mutation (69). A second α4 mutation was later found in a Norwegian family (68).…”

Section: Ligand-gated Acetylcholine Receptorsmentioning

confidence: 69%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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“…Whereas the frontal lobe origin, adolescent onset, and clusters of nocturnal, hyperkinetic motor seizures are signatures of this disorder, the ADNFLE seizure phenotype shows incomplete penetrance and can present with (6,8) or without (4, 9) intra-and interfamilial variation in expressivity.…”

mentioning

confidence: 99%

“…However, studies in heterologous expression systems designed to discover a shared, altered property that might explain the neuronal network dysfunction underlying ADNFLE seizures have lead to both ''gain-of-function'' (10-12) and ''loss-of-function'' (8,13,14) models. The effect of stimulating nAChRs (mutant or otherwise) on cortical network activity is difficult to predict, hence, insight into the mechanism responsible for neuronal synchrony and epileptogenesis in ADNFLE must necessarily come from models that attempt to reconstitute the in vivo distribution and function of mutant nAChRs.…”

mentioning

confidence: 99%

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Klaassen

Glykys

Maguire

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

184

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Selected mutations in the human ␣4 or ␤2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4 S252F and Chrna4 ؉L264 ) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II͞III cortical pyramidal cells reveal a >20-fold increase in nicotineevoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent ␥-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant ␣4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.cortex ͉ GABAegic interneuron ͉ nicotinic acetylcholine receptor E pilepsy is a common neurological disorder affecting Ϸ1% of the population worldwide. Over the past decade, several idiopathic epilepsies have been identified that show single-gene inheritance. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first idiopathic epilepsy for which specific mutations were described (1). Segregation and subsequent linkage analyses of ADNFLE families led to the assignment of candidate genetic loci and ultimately to the identification of specific mutations. Two of the three loci associated with this partial epilepsy (ENFL1, 20q13.3 and ENFL3, 1p21) map to neuronal nicotinic acetylcholine receptor (nAChR) subunit genes ␣4 and ␤2 (CHRNB2), respectively. A candidate gene for the third locus (ENFL2, 15q24) has not been identified. Considerable clinical and genetic data now provide a strong link between the ADNFLE syndrome and six mutations located within the pore-forming, second transmembrane domain of the ␣4 (S252F, ϩL264, S256L, T265I) and ␤2 (V287L, V287M) nAChR subunits (2), as well as a single mutation located in the third transmembrane domain of the ␤2 subunit (I312M) (3).In most patients with ADNFLE, seizure onset occurs during adolescence with symptoms persisting into adulthood. Affected individuals typically present without adverse neurological symptoms other than seizures, although several reports describe ADNFLE patients with a concomitant history of psychiatric problems (4, 5), cognitive deficits (3), or mental retardation (6). Clinical features of ADNFLE include clusters of brief seizures that initiate during non-rapid eye movement (NREM) sle...

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“…3 and 4). Mutations within the voltage-gated potassium channel subunits KCNQ2 and KCNQ3 cause the benign familial neonatal convulsions phenotype (5-9), whereas mutations in the acetylcholine ligand-gated receptor family are responsible for familial nocturnal frontal lobe epilepsy (10)(11)(12)(13)(14). In vitro investigations with the oocyte expression system and two-electrode voltage-clamp assay generally suggest that these mutations would result in neuronal hyperexcitability.…”

mentioning

confidence: 99%

Altered kinetics and benzodiazepine sensitivity of a GABA _A receptor subunit mutation [γ ₂ (R43Q)] found in human epilepsy

Bowser

Wagner

Czajkowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

105

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The ␥-aminobutyric acid type A (GABAA) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA A receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-toglutamine mutation at position 43 within the GABAA ␥2-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABAA receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from ␣1␤2␥2 or ␣1␤2␥2(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA A receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.rapid agonist application ͉ two-electrode voltage clamp ͉ Xenopus oocytes E pilepsy, one of the most common neurological disorders, is characterized by episodic seizures that are caused by paroxysmal, synchronized discharges of hyperexcitable neuronal populations. Many human epileptic syndromes have a genetic component, and the molecular basis of a few inherited epilepsies is now known (1). Most genes implicated in epilepsy to date code for ion channel subunits, both ligand-gated and voltage-gated (2). For example, mutations within the ␣-and ␤-subunits of the voltage-gated sodium channel family have been found in families with generalized epilepsy with febrile seizures plus (GEFSϩ; refs. 3 and 4). Mutations within the voltage-gated potassium channel subunits KCNQ2 and KCNQ3 cause the benign familial neonatal convulsions phenotype (5-9), whereas mutations in the acetylcholine ligand-gated receptor family are responsible for familial nocturnal frontal lobe epilepsy (10)(11)(12)(13)(14). In vitro investigations with the oocyte expression system and two-electrode voltage-clamp assay generally suggest that these mutations would result in neuronal hyperexcitability.The ␥-aminobutyric acid type A (GABA A ) receptor is the predominant ligand-gated Cl Ϫ ion channel conferring fast inhibitory synaptic transmission in the CNS and, therefore, is a prime candidate for involvement in epileptogenesis. The GABA A receptor is a heterooligomeric complex of five subunits. Each subunit has a large, N-terminal extracellular domain, four transmembrane domains, and a small, extracellular C-terminal tail. Multiple subunits have been cloned and divided into...

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An Insertion Mutation of the CHRNA4 Gene in a Family With Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Cited by 339 publications

References 23 publications

Identification of Epilepsy Genes in Human and Mouse

Identification of Epilepsy Genes in Human and Mouse

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Altered kinetics and benzodiazepine sensitivity of a GABA _A receptor subunit mutation [γ ₂ (R43Q)] found in human epilepsy

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An Insertion Mutation of the CHRNA4 Gene in a Family With Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Cited by 339 publications

References 23 publications

Identification of Epilepsy Genes in Human and Mouse

Identification of Epilepsy Genes in Human and Mouse

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Altered kinetics and benzodiazepine sensitivity of a GABA A receptor subunit mutation [γ 2 (R43Q)] found in human epilepsy

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Altered kinetics and benzodiazepine sensitivity of a GABA _A receptor subunit mutation [γ ₂ (R43Q)] found in human epilepsy