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

doi:10.1016/j.nbd.2005.05.013

Neurobiology of Disease

Volume 20, Issue 3, December 2005, Pages 799-804

https://doi.org/10.1016/j.nbd.2005.05.013 Get rights and content

Abstract

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.

Introduction

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clustered attacks of brief motor seizures originating from the frontal lobe mostly during light sleep (Scheffer et al., 1995). The onset of the epilepsy is usually during childhood or adolescence, with a penetrance of 70–80%. Seizures are often, but not in all patients readily controlled by antiepileptic drugs, especially carbamazepine. Two genes have so far been identified in ADNFLE families (Fusco et al., 2000, Hirose et al., 1999, Leniger et al., 2003, Phillips et al., 2001, Steinlein et al., 1995), CHRNA4 and CHRNB2 encoding the α4 and β2 subunits of the nAChR, respectively. The nAChRs are members of the large family of ligand-gated ion channels and are constituted by the assembly of five subunits arranged pseudosymmetrically around the central axis that forms a cation-selective ion pore. Pharmacological and ligand-binding studies have shown that the different nAChRs vary in their distribution in brain and channel properties, depending on their subunit composition (Bertrand et al., 2002). Both α4 and β2 subunits are found in almost all brain regions, and the heteromeric α4₂/β2₃ receptor is thought to be the major high-affinity nicotine nAChR subtype in mammalian brain. In support of the recognized importance of the cholinergic system in higher brain functions, recent work has shown that nAChR mutations not only cause epilepsy but also can be associated with additional neurological or psychiatric features (Hirose et al., 1999, Cho et al., 2003, Magnusson et al., 2003). We present herein a new ADNFLE mutation in the CHRNB2 gene that is characterized by an unusual localization at the β2 protein level, and a clinical phenotype including nocturnal seizures and selective defects in memory performances.

Section snippets

Patients and controls

Clinical data, results from neuropsychometric testing (performed at age 14 years), video-electroencephalography (video-EEG), MRI results, and DNA samples were obtained from both twin sisters (III3, III4, Fig. 1), now age 17. The parents (II1, II2) but not the twin's two older brothers (III1, III2) (age 23 and 19 years) were available for DNA testing.

Mutation analysis

DNA samples from both affected twins were used to screen the whole coding region of CHRNB2 for mutations. Primer pairs and PCR conditions have been

Clinical history

The twins (III3, III4, Fig. 1) were born following a normal pregnancy by cesarean section at 35 weeks. Both had normal motor development but needed speech therapy and were diagnosed as being dyslexic early. At the age of 7 years, nocturnal seizures started in both twins within a month. Initially, seizures occurred every 20 min throughout the night, and also during daytime naps. Therapy with sodium valproate stopped seizures for 4 to 5 years. Seizures recurred in both girls within months,

Discussion

The most interesting aspects of the nAChR mutation I312M are its unusual localization in the M3 segment of the β2 subunit and its association with both epilepsy and specific cognitive defects. The mutation was not found in the parents but occurred de novo in the twins. Both twins had specific problems with verbal memory tasks. Their performances in learning and recalling verbal material were significantly lower than expected from their general IQ. Such severe memory problems were not present in

Acknowledgments

This work was supported by a grant from the Nationales Genomforschungsnetz 2 (NGFN2) to OKS and by the Swiss National Science Foundation to DB.

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Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By modulating cation flux across cell membranes, neuronal nAChRs regulate neuronal excitability and the release of a variety of neurotransmitters to influence multiple physiologic and behavioral processes including synaptic plasticity, motor function, attention, learning and memory. Abnormalities of neuronal nAChRs have been implicated in the pathophysiology of neurologic disorders including Alzheimer’s disease, Parkinson’s disease, epilepsy, and Tourette´s syndrome, as well as psychiatric disorders including schizophrenia, depression, and anxiety. The potential role of nAChRs in a particular illness may be indicated by alterations in the expression of nAChRs in relevant brain regions, genetic variability in the genes encoding for nAChR subunit proteins, and/or clinical or preclinical observations where specific ligands showed a therapeutic effect. Over the past 25 years, extensive preclinical and some early clinical evidence suggested that ligands at nAChRs might have therapeutic potential for neurologic and psychiatric disorders. However, to date the only approved indications for nAChR ligands are smoking cessation and the treatment of dry eye disease. It has been argued that progress in nAChR drug discovery has been limited by translational gaps between the preclinical models and the human disease as well as unresolved questions regarding the pharmacological goal (i.e., agonism, antagonism or receptor desensitization) depending on the disease.
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Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.
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Citation Excerpt :
Interestingly, several mutations in the AchRs subunit genes CHRNA4, CHRNB2, and CHRNA2 have been reported in families with ADNFLE [95]. Moreover, Bertrand et al. discovered a mutation in the β2 nAChR in a pair of monozygotic twins who exhibited verbal memory disabilities [96]. Subsequently, Picard et al. identified three mutations in the CHRNA4 gene and one mutation in the CHRNB2 gene in 11 patients who presented with memory decline and executive dysfunction [94].
Epilepsy is a common neurological disease characterized by recurrent seizures. About 70 million people were affected by epilepsy or epileptic seizures. Epilepsy is a complicated complex or symptomatic syndromes induced by structural, functional, and genetic causes. Meanwhile, several comorbidities are accompanied by epileptic seizures. Cognitive dysfunction is a long-standing complication associated with epileptic seizures, which severely impairs quality of life. Although the definitive pathogenic mechanisms underlying epilepsy-related cognitive dysfunction remain unclear, accumulating evidence indicates that multiple risk factors are probably involved in the development and progression of cognitive dysfunction in patients with epilepsy. These factors include the underlying etiology, recurrent seizures or status epilepticus, structural damage that induced secondary epilepsy, genetic variants, and molecular alterations. In this review, we summarize several theories that may explain the genetic and molecular basis of epilepsy-related cognitive dysfunction.
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Previously characterized nicotinic acetylcholine receptor (nAChR) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-associated mutations are found in α2, α4 and β2 subunit transmembrane (TM) domains. They predominantly increase ACh potency and, for β2-subunit mutants, increase macroscopic currents. Two recently-identified mutations, α4(R336H) and β2(V337G), located in the intracellular cytoplasmic loop (C2) have been associated with non-familial NFLE. Effects of these mutations on α4β2-nAChR function and expression were studied for the first time, using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Biased-ratio preparations elucidated the mutations' effects at alternate isoforms: high-sensitivity [HS; (α4)₂(β2)₃] or low-sensitivity [LS; (α4)₃(β2)₂] via 1:10 or 30:1 [α4:β2] cRNA injection ratios, respectively. An unbiased (1:1 [α4:β2] cRNA) injection ratio was also used to study potential shifts in isoform expression. α4(R336H)-containing receptors showed significant increases in maximal ACh-induced currents (I_max) in all preparations (140% increase compared to wild type control). β2(V337G)-containing receptors significantly increased I_max in the LS-favoring preparation (20% increase compared to control). Expression of either mutation consistently produced enrichment of HS-isoform expression in all preparations. α4β2-nAChR harboring either NFLE mutant subunit showed unchanged ACh, sazetidine-A, nicotine, cytisine and mecamylamine potency. However, both mutant subunits enhanced partial agonist efficacies in the LS-biased preparation. Using β2-subunit-specific [¹²⁵I]mAb 295 immunolabeling, nAChR cell-surface expression was determined. Antibody binding studies revealed that the β2(V337G) mutation tended to reduce cell-surface expression, and function per receptor was significantly increased by either NFLE mutant subunit in HS-favoring preparations. These findings identify both common and differing features between TM- and C2-domain AD/NFLE-associated mutations. As we discuss, the shared features may be particularly salient to AD/NFLE etiology.
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Focal epilepsies were for a long time thought to be acquired disorders secondary to cerebral lesions. However, the important role of genetic factors in focal epilepsies is now well established. Several focal epilepsy syndromes are now proven to be monogenic disorders. While earlier genetic studies suggested a strong contribution of ion channel and neurotransmitter receptor genes, later work has revealed alternative pathways, among which the mammalian target of rapamycin (mTOR) signal transduction pathway with DEPDC5. In this article, we provide an update on the mutational spectrum of neuronal nicotinic acetylcholine receptor genes (CHRNA4, CHRNB2, CHRNA2) and KCNT1 causing autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and of LGI1 in autosomal dominant epilepsy with auditory features (ADEAF). We also emphasize, through a review of the current literature, the contribution of in vitro and in vivo models developed to unveil the pathogenic mechanisms underlying these two epileptic syndromes.

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¹: Contributed equally.

View full text

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

Abstract

Introduction

Section snippets

Patients and controls

Mutation analysis

Clinical history

Discussion

Acknowledgments

Behav. Brain. Res.

Trends Pharmacol. Sci.

Neurobiol. Learn. Mem.

Biophys. J.

Neuroscience

Neurobiol. Learn. Mem.

Am. J. Hum. Genet.

Neurobiol. Learn. Mem.

FEBS Lett.

How mutations in the nAChRs can cause ADNFLE epilepsy

Epilepsia

Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions

Hum. Genet.

A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) presenting as partial seizures with mental retardation

Arch. Neurol.