Molecular Basis of Inherited Epilepsy

BASIC SCIENCE SEMINARS IN NEUROLOGY

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Molecular Basis of Inherited Epilepsy

Alfred L. George, Jr, MD

pilepsy is a common, paroxysmal, and heterogeneous neurological disorder. Many factors, including complex genetic influences, contribute to the pathogenesis of epilepsy. However, several epilepsy syndromes are caused by mutations in single genes (Table). Most epilepsy-associated genes that have been identified within the past 5 years en- Ecode ion channels. This review illustrates the progress in defining the molecular basis of inherited epilepsies and highlights conditions caused by dysfunctional ion channels.

Ion channels may be broadly classified as dreds. The use of genetic linkage analysis voltage or ligand gated, depending on has become the traditional approach to whether the primary stimulus for their ac- search for genes responsible for Mende- tivity is a change in local membrane po- lian disorders (ie, caused by a single gene), tential or a chemical messenger (eg, neu- an approach called positional cloning. In rotransmitter). The role of ion channels positional cloning, once linkage is estab- in neuronal excitability is well estab- lished with a chromosomal region that har- lished, and the identification of muta- bors the disease-causing gene, the next tions in neuronal ion channel genes linked challenge becomes identifying all of the to inherited epilepsy emphasizes the deli- protein-coding segments within that re- cate balances that maintain electrical har- gion. As the entire human genome se- mony in the central nervous system. These quence is now available, this process re- discoveries have also revealed new ap- quires only a few hours of database mining proaches to diagnosis and disease catego- using a desktop computer. For many of the rization, with the ultimate hope of new, inherited epilepsies, candidate genes (ie, gene-specific therapeutics. genes encoding proteins potentially in- volved in neuronal excitability) within the IDENTIFYING AND critical regions identified by linkage analy- CHARACTERIZING sis were readily evident. EPILEPSY GENES To make the final link between a gene and epilepsy, mutations must be discov- Molecular Genetic Approaches ered in affected individuals. This is typi- to Finding Epilepsy Genes cally accomplished by means of DNA se- quencing or a variety of screening methods Many recent contributions to our knowl- such as single-strand conformational analy- edge regarding the molecular basis of in- sis. Mutations are extremely rare DNA vari- herited epilepsy, especially with regard to ants or polymorphisms that seldom occur ion channel disorders, have exploited the in unaffected individuals. A variety of mu- combination of experimental paradigms tations are easily recognized by virtue of from genetics and physiology (Figure). their deleterious effects on the encoded pro- Initially, genetic linkage analysis pin- tein. Obvious mutations include prema- pointed regions of the human genome ture stop codons (nonsense mutation), in- where polymorphic markers segregate with sertion or deletion of nucleotides that alter epilepsy in large, multigenerational kin- the reading frame (frameshift errors), and errors that disrupt signals important for From the Division of Genetic Medicine, Departments of Medicine and Pharmacology, splicing messenger RNA (mRNA) (splice- Vanderbilt University, Nashville, Tenn. site mutations). However, many muta-

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Chromosomal Syndrome (OMIM No.) Locus Gene Gene Product BNFC BNFC type 1 (121200) 20q13.2 KCNQ2 Voltage-gated potassium channel, ␣ subunit BNFC with myokymia (606437) 20q13.2 KCNQ2 Voltage-gated potassium channel, ␣ subunit BNFC type 2 (121201) 8q24 KCNQ3 Voltage-gated potassium channel, ␣ subunit Benign familial neonatal infantile seizures (607745) 2q24 SCN2A Voltage-gated sodium channel, ␣ subunit Febrile seizures

GEFS+ type 1 (604233) 19q13.1 SCN1B Voltage-gated sodium channel, ␤1 subunit GEFS+ type 2 (604233) 2q24 SCN1A Voltage-gated sodium channel, ␣ subunit

GEFS+ type 3 (604233) 5q31.1-q33.1 GABRG2 GABAA receptor, ␥2 subunit Febrile seizures associated with afebrile seizures (604233) 2q24 SCN2A Voltage-gated sodium channel, ␣ subunit Severe myoclonic epilepsy of infancy, Dravet syndrome (607208) 2q24 SCN1A Voltage-gated sodium channel, ␣ subunit Intractable childhood epilepsy with frequent generalized 2q24 SCN1A Voltage-gated sodium channel, ␣ subunit tonic-clonic seizures Familial febrile convulsions type 4 (604352) 5q14 MASS1 Monogenic audiogenic seizure-susceptible gene ADNFLE

ADNFLE type 1 (600513) 20q13.2-q13.3 CHRNA4 nAChR, ␣4 subunit ADNFLE type 2 (603204) 15q24 ? ?

ADNFLE type 3 (605375) 1q21 CHRNB2 nAChR, ␤2 subunit Absence epilepsy Childhood absence epilepsy type 1 (600131) 8q24 ? ?

Childhood absence epilepsy type 2 and febrile seizures (607681) 5q31.1-q33.1 GABRG2 GABAA receptor, ␥2 subunit Childhood absence epilepsy type 3 (607682) 3q27.1* CLCN2 Voltage-gated chloride channel Juvenile absence epilepsy (607631) 3q27.1* CLCN2 Voltage-gated chloride channel Myoclonic epilepsy

Autosomal dominant juvenile myoclonic epilepsy (606904) 5q34-q35 GABRA1 GABAA receptor, ␣1 subunit Juvenile myoclonic epilepsy (606904) 3q27.1* CLCN2 Voltage-gated chloride channel

Juvenile myoclonic epilepsy (606904) 2q22-2q23 CACNB4 Voltage-gated calcium channel, ␤4 subunit Myoclonic epilepsy of Unverricht and Lundborg (254800) 21q22.3 CSTB Cystatin B Myoclonic epilepsy of Lafora (254780) 6q24 EPM2A Protein tyrosine phosphatase (laforin) Benign adult familial myoclonic epilepsy (601068) 8q24 ? ? Other epilepsy syndromes Epilepsy with grand mal seizures on awakening (607628) 3q27.1* CLCN2 Voltage-gated chloride channel Autosomal dominant lateral temporal lobe epilepsy (600512) 10q24 LGI1 Leucine-rich gene, glioma inactivated X-linked infantile spasm syndrome, West syndrome (308350) Xp22.13 ARX Aristaless-related homeobox gene X-linked infantile spasm syndrome, West syndrome (308350) Xp22.13 STK9 Serine/threonine kinase 9

Abbreviations: ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; BNFC, benign familial neonatal convulsions; GABA, ␥-aminobutyric acid; GEFS+, generalized epilepsy with febrile seizures plus; nAChR, nicotinic acetylcholine receptors; OMIM, Online Mendelian Inheritance in Man database (available at: http://www.ncbi.nlm.nih.gov/Omim/); question mark, unknown. *Indicates the cytogenetic location was refined (database available at: http://genome.uscs.edu).

tions alter a single nucleotide in the damental functional defects con- cells (approximately 1 mm in diam- gene sequence, leading to a change in ferred by these gene variants. In vivo eter) can then be used in simple elec- 1 amino acid (missense mutation). In studies of human neuronal ion chan- trophysiologic experiments (ie, many cases, disease-causing mis- nels are experimentally challeng- 2-electrode voltage-clamp recording). sense mutations are difficult to dis- ing. Therefore, research in this area Xenopus oocytes are easy and inex- tinguish from benign amino acid sub- has exploited recombinant (cloned) pensive to use, but expression of en- stitutions associated with common ion channels that can be manipu- dogenous ion channels can interfere polymorphisms. In this context, ad- lated and studied in a controlled with the examination of recombi- ditional experimental paradigms are laboratory environment. Recombi- nant proteins, and they are not cells required to assess the function of the nant ion channels are DNA copies of human origin. Another type of variant protein, usually through the of the corresponding human mRNA expression system uses cultured use of recombinant genes expressed that can be introduced into cells to human or mammalian cells (eg, in the laboratory. enable functional expression of the HEK-293 [human embryonic kid- encoded protein. ney cells]) and a more precise method Characterizing the Molecular Two cell systems are com- of electrophysiologic analysis (patch- Physiology of Mutant Ion monly used for expression of recom- clamp recording). Cultured cells have Channels in Epilepsy binant ion channels: frog oocytes and specific advantages over Xenopus oo- cultured mammalian cells. Oocytes cytes, including improved experimen- The discovery of ion channel muta- from the frog Xenopus laevis are large tal control and a human or mamma- tions associated with inherited enough to be directly injected with lian cellular environment. However, epilepsy prompted a series of ex- synthetic mRNA derived from a re- no in vitro system provides a perfect periments designed to reveal the fun- combinant ion channel. These large model for living brain tissue, and

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G G G G A T C G C A C G C

SCN1A

Linkage Analysis Mutation Screening

E Recombinant D Ion Channel Transfection of Cultured Cells

D1 D2 D3 D4

INa

Patch Clamp Site-Directed Mutagenesis Electrophysiology

Illustrations of experimental approaches used to identify and characterize epilepsy genes. A, Linkage analysis uses large, multigenerational kindreds segregating an epilepsy phenotype. The shaded pedigree symbols represent affected individuals. Pairs of vertical lines beneath each pedigree symbol represent hypothetical alleles or haplotypes (designated by different colors) at a specific chromosomal region. An asterisk marks the allele or haplotype that segregates with the disease. Circles indicate female members; squares, male. B, Chromosome 2 ideogram illustrating the location of a single epilepsy-associated gene (SCN1A) identified by linkage analysis. C, Representative DNA sequence trace demonstrating a heterozygous mutation (C/T) that illustrates an approach to mutation screening. D, Simplified model of the SCN1A voltage-gated sodium channel illustrating the use of a recombinant ion channel for functional characterization of an epilepsy-associated mutation (pink circle). E, Functional characterization of a recombinant, mutant sodium channel using cultured mammalian cells and patch-clamp recording. The DNA encoding a recombinant ion channel is introduced into cultured cells by transfection (droplets represent transfection reagent).

A single cell is illustrated undergoing patch-clamp recording and resulting in a typical sodium current (INa).

therefore we should extrapolate ob- ample, generalized epilepsy with fe- of the inherited epilepsies and may servations made in these experimen- brile seizures plus (GEFS+) is asso- provide valuable new information for tal systems to human neurophysiol- ciated with mutations in 2 distinct reassessing their classification. Spe- ogy with caution. voltage-gated sodium channel genes cific illustrations are discussed in the (SCN1B and SCN1A) or in the gene following subsection. ADVANCES IN encoding the ␥2 subunit of ␥-amino- UNDERSTANDING SPECIFIC butyric acid (GABAA) receptors Epilepsy Associated EPILEPSY SYNDROMES (GABRG2). Mutations of another so- With Voltage-Gated dium channel gene (SCN2A) are as- Potassium Channels The Table provides the genetic basis sociated with a very similar syn- of specific inherited epilepsy syndrome. Other examples of genetic The syndrome of benign familial neo- dromes. Among the 28 listed disor- heterogeneity include autosomal natal convulsions (BFNC) is a rare in- ders, 19 are associated with muta- dominant nocturnal frontal lobe epi- herited form of idiopathic general- tions of genes encoding 11 different lepsy (ADNFLE), caused by muta- ized epilepsy exhibiting autosomal ion channels and 6 other genes that tions in genes encoding different sub- dominant inheritance. Convulsions have less well-defined functions. units of nicotinic acetylcholine occur in the neonatal period and typi- There is considerable genetic hetero- receptors (nAChRs), and childhood cally resolve spontaneously after a geneity among the inherited epilep- absence epilepsy, caused by muta- few weeks of life. In very rare cases, a sies. In other words, the same clini- tions of the CLCN2 chloride chan- seizure disorder may occur in adult- cal syndrome may be caused by nel gene or GABRG2. These observa- hood. The syndrome of BFNC is mutations of different genes. For ex- tions illustrate the genetic complexity genetically heterogeneous with iden-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 ␣ tified loci on chromosomes 8q and These findings suggest that in some coding distinct nAChR subunits ( 4 ␤ 20q. In 1998, 2 groups identified the cases, SCN1A mutations promote a and 2) have been associated with potassium channel gene KCNQ2 as gain of function in sodium channels, ADNFLE.28 A third genetic locus has the 20q gene and KCNQ3 as respon- leading to neuronal hyperexcitabil- been identified near a cluster of other sible for the chromosome 8q-linked ity. Other SCN1A mutations associ- nAChR subunit genes (15q24), but syndrome.1,2 Both potassium chan- ated with GEFS+ cause other types of mutations linked to this form of the nels exhibited a high degree of amino functional impairments that may lead disease have not yet been discov- acid sequence identity with KCNQ1, to loss of function.16,20 Whether gain ered. Neuronal nAChRs are lo- a voltage-gated potassium channel of sodium channel function in excit- cated in presynaptic membranes of gene previously linked to congenital atory neurons or loss of function in the cerebral cortex, where they fa- long QT syndrome, an inherited car- inhibitory neurons is the primary cilitate excitatory and inhibitory neu- diac arrhythmia.3 The KCNQ2 and mechanism responsible for epilepsy rotransmitter release. KCNQ3 potassium channels coas- in GEFS+ remains unclear. Functional characterization of semble to generate potassium chan- Severe myoclonic epilepsy of in- mutant nAChR subunits in Xenopus nels that generate ionic currents re- fancy is a rare convulsive disorder oocytes has suggested a loss or a gain sembling neuronal M-currents.4 characterized by febrile seizures with of receptor function,29 making it dif- Neuronal M-currents modulate ex- onset during the first year of life fol- ficult to determine the precise mo- citability by dampening the ten- lowed by intractable epilepsy, im- lecular mechanism underlying dency for repetitive firing. Neuronal paired psychomotor development, ADNFLE. A recent study revealed 21,22 ␣ ␤ M-currents are inhibited by musca- and ataxia. Seizures in this disor- that mutations in the 4 and 2 rinic acetylcholine receptor agonists der are usually unresponsive to an- nAChR subunits interfere with cal- and activators of other types of neu- ticonvulsant drugs. Recently, sev- cium ion modulation of receptor rotransmitter receptors. Mutations in eral heterozygous SCN1A mutations, function in a dominant manner, sug- KCNQ2 or KCNQ3 reduce function including several instances of de novo gesting an alternative explanation for of the encoded potassium channel by mutations, have been reported in pro- ADNFLE.30 Acetylcholine activa- ␣ ␤ a dominant-negative mechanism con- bands with severe myoclonic epi- tion of wild-type 4 and 2 recep- sistent with the autosomal domi- lepsy of infancy, including mis- tors is normally potentiated by ex- nant inheritance pattern of BFNC.5 sense, nonsense, and insertion/ tracellular calcium ions. In rapidly deletion alleles.23-26 The observed firing excitatory synapses, postsyn- Epilepsy Associated With clinical similarities between severe aptic glutamate receptors deplete Voltage-Gated Sodium Channels myoclonic epilepsy of infancy and local extracellular calcium ions GEFS+, including the frequent oc- and reduce calcium potentiation of In 1997, Scheffer and Berkovic6 de- currence of febrile seizures and nAChRs, a possible negative feed- scribed GEFS+, a newly recognized shared molecular genetic origins, back mechanism to limit further pre- epilepsy syndrome with autosomal have prompted the idea that the 2 dis- synaptic glutamate release. This feed- dominant inheritance. The syn- orders represent a spectrum of se- back mechanism may be disabled in drome was named in reference to the verity of the same disease.27 Many presynaptic membranes expressing ␣ ␤ common occurrence of febrile sei- SCN1A mutations associated with mutant 4 and 2 receptors, possi- zures in early childhood that often this disorder seem to encode non- bly leading to increased excitatory persisted beyond 6 years of age. In ad- functional sodium channels, lead- neurotransmitter release under some dition to febrile seizures, affected adult ing to the suggestion that severe myo- conditions such as rapid synchro- members of GEFS+ families exhib- clonic epilepsy of infancy is caused nous neuronal firing during sleep.30 ited afebrile seizures and seizures with by loss-of-function mutations. multiple clinical phenotypes. Mis- Epilepsies Associated With sense mutations in SCN1A encoding Autosomal Dominant Nocturnal Voltage- and Ligand-Gated a neuronal voltage-gated sodium Frontal Lobe Epilepsy Chloride Channels channel ␣ subunit account for most GEFS+ cases,7-11 but heritable de- Individuals affected with ADNFLE There is a common notion that sei- fects in 2 other sodium channel genes experience short, partial seizures dur- zures occur because of imbalances be- (SCN1B and SCN2A)12,13 and a GABA ing sleep. Episodes often occur in tween excitatory and inhibitory neu- 14,15 receptor subunit gene (GABRG2) clusters, localize to the frontal lobes ronal activity in the brain. The GABAA can also cause the disorder or clini- in ictal electroencephalographic re- receptors are critical mediators of cally similar conditions. cordings, and involve nonspecific au- inhibitory neural activity. In the The functional properties of mu- ras along with brief motor seizures. healthy postnatal brain, activation of tant neuronal sodium channels asso- Most cases are mild and respond well GABAA receptors triggers an influx of ciated with inherited epilepsy have to carbamazepine treatment. chloride ions that render the post- been described previously.16-20 Three Neuronal nAChRs are penta- synaptic membrane potential more SCN1A mutations associated with meric complexes with variable sub- negative (hyperpolarization). This GEFS+ exhibit defects in fast inacti- unit composition. The most com- hyperpolarization counters excit- vation gating characterized by a per- mon nAChR composition contains atory synaptic inputs that would oth- ␣ ␤ sistent, noninactivating current dur- 4 and 2 subunits. Mutations in 2 erwise depolarize the postsynaptic ing membrane depolarizations.17 genes (CHRNA4 and CHRNB2) en- membrane and promote action po-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 modulated KCNQ2/KCNQ3 K+ channels causes tential firing. The ability of GABAA re- tinct cellular mechanisms may ac- ceptors to mediate chloride influx is count for epilepsy associated with dif- epilepsy. Nature. 1998;396:687-690. 6. Scheffer IE, Berkovic SF. Generalized epilepsy with dependent on other factors, includ- ferent CLCN2 mutations. febrile seizures plus: a genetic disorder with het- ing potassium-chloride cotransport- erogeneous clinical phenotypes. Brain. 1997; ers and voltage-gated chloride chan- RELEVANCE TO 120(pt 3):479-490. nels that maintain a low intracellular NEUROSCIENCE AND THE 7. Escayg A, MacDonald BT, Meisler MH, et al. Mu- PRACTICE OF NEUROLOGY tations of SCN1A, encoding a neuronal sodium concentration of this anion. channel, in two families with GEFS+2. Nat Genet. Mutations in 2 genes that en- 2000;24:343-345. code subunits of GABAA receptors By defining the molecular basis of 8. Escayg A, Heils A, MacDonald BT, Haug K, Sander and a third gene that encodes a volt- uncommon Mendelian epilepsy syn- T, Meisler MH. A novel SCN1A mutation associ- age-gated chloride channel have been dromes, we identify genes that may ated with generalized epilepsy with febrile seizures plus and prevalence of variants in patients associated with inherited epilepsy. contribute to epileptogenesis in more with epilepsy. Am J Hum Genet. 2001;68:866- The GABAA receptors are composed common and genetically complex 873. of 5 subunits encoded by multiple dif- forms of the disease. Similarly, by 9. Abou-Khalil B, Ge Q, Desai R, et al. Partial epi- ferent gene families (␣, ␤, ␥, ␦, ⑀, ␲, studying the physiological impact of lepsy and generalized epilepsy with febrile sei- and ␪) with a predominance of com- specific mutations, we discover the zures plus and a novel SCN1A mutation. Neurol- ogy. 2001;57:2265-2272. plexes containing combinations of diversity of cellular mechanisms that 10. Wallace RH, Scheffer IE, Barnett S, et al. Neuro- ␣␤␥ or ␣␤␦. The gene encoding the can promote neuronal hyperexcit- nal sodium-channel a1-subunit mutations in gen- ␣ 1 subunit (GABRA1) has been linked ability and learn more about the im- eralized epilepsy with febrile seizures plus. Am J to an autosomal dominant form of ju- portance of genes expressed in the Hum Genet. 2001;68:859-865. venile myoclonic epilepsy. Muta- brain. These advances also contrib- 11. Sugawara T, Mazaki-Miyazaki E, Ito M, et al. Nav1.1 ␥ mutations cause febrile seizures associated with tions in GABRG2 encoding the 2 ute to our ability to recognize and afebrile partial seizures. Neurology. 2001;57:703- subunit have been associated with diagnose inherited neurological dis- 705. GEFS+ and the syndrome of child- eases, provide important informa- 12. Wallace RH, Wang DW, Singh R, et al. Febrile sei- hood absence epilepsy with febrile tion useful for counseling affected zures and generalized epilepsy associated with a + seizures.14,31 Functional character- families, and identify potential new mutation in the Na -channel b1 subunit gene SCN1B. Nat Genet. 1998;19:366-370. ization of GABAA receptor subunit targets for anticonvulsant therapy. 13. Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A mutations in Xenopus oocytes and missense mutation of the Na+ channel aII sub- cultured mammalian cells demon- Accepted for publication November 3, unit gene Nav1.2 in a patient with febrile and afe- strated impaired receptor activity in 2003. brile seizures causes channel dysfunction. Proc vitro, suggesting reduced GABA- Natl Acad Sci U S A. 2001;98:6384-6389. This study was supported by 14. Wallace RH, Marini C, Petrou S, et al. Mutant mediated synaptic inhibition as a pri- Javits Neuroscience Investigator GABAA receptor g2-subunit in childhood ab- mary cause for neuronal hyperexcit- Award NS32387 from the National In- sence epilepsy and febrile seizures. Nat Genet. ability.32 stitute of Neurological Disorders and 2001;28:49-52. The third gene encoding a chlo- Stroke, Bethesda, Md. 15. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First ride-transporting protein associated genetic evidence of GABAA receptor dysfunction I thank Christopher Lossin, PhD, in epilepsy: a mutation in the gamma2-subunit with inherited epilepsy is CLCN2. The for critical reading of the manu- gene. Nat Genet. 2001;28:46-48. gene CLCN2 encodes a chloride chan- script. 16. Spampanato J, Escayg A, Meisler MH, Goldin AL. nel that is widely distributed in the Corresponding author: Alfred L. Functional effects of two voltage-gated sodium nervous system and has a suspected George, Jr, MD, Division of Genetic channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J Neuro- role in neuronal excitability. Muta- Medicine, 529 Light Hall, Vanderbilt sci. 2001;21:7481-7490. tions in CLCN2 have been associ- University, Nashville, TN 37232- 17. 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Call for Papers

apers are invited for a JAMA/ARCHIVES joint theme P issue on Medical Applications of Biotechnology in early 2005. Please submit papers on pertinent to neurological applications of biotechnology: neuroimaging; la- ser capture microdissection; stem cells; microarrays for DNA, RNA, or protein; DNA polymorphisms; genetic en- gineering; nanotechnology; neuroprosthetics for vi- sion, hearing, and movement; and other important emerg- ing biotechnologies that enhance new therapies. Papers received by June 30, 2004, have the best chance of ac- ceptance.

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