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Genetics in Epilepsy Experimental Neurobiology Vol. 12, pages 71～80, December 2003 Genetics in Epilepsy Chang-Ho Yun1,* and Beom S. Jeon2 1Department of Neurology, College of Medicine, Inha University, Incheon 400-711, Korea, 2Department of Neurology, Seoul National University College of Medicine, Seoul 110-744, Korea ABSTRACT The importance of genetic contributions to the epilepsies is now well established. Mutations in over 70 genes now define biological pathways leading to the epilepsy. These mutations disrupt a very large spectrum of biologic function. Some of the in- herited errors alter the intrinisic ion channel properties directly responsible for neuronal hyperexcitability and others have impact on the brain development or cellular regulation. This paper reviews the pathogenic implications of the established genetic mutations and briefly mentioned the susceptible genes in hereditary or familial epilepsy syndrome. Key words: Genetic, epilepsy INTRODUCTION causing epilepsies. Once the abnormalities such as genes and their products are identified, it will lead Epilepsy affects more than 0.5% of the general to an understanding of how the alterations in indi- population and has a significant hereditary compo- vidual neuronal or neural network properties cause nent. Twin studies that report concordance rates epilepsy (Delgado-Escueta et al., 1994). Probably consistently higher in monozygotic (MZ) than in di- less than 1% of patients with epilepsy are found to zygotic (DZ) twins provides strong support for a ge- have a seizure disorder caused by a single gene netic role in epilepsy (Berkovic et al., 1998). Con- mutation. The vast majority of epilepsy cases are cordance rates ranged from 10.8% in MZ pairs with considered complex traits, a combination of environ- acquired brain injuries to 70% in those without these mental factors and multiple genetic influences. Dis- defects. In DZ twins, concordance ranged from 3 to ease causing mutations have been discovered in 10%, regardless of a brain injury in the affected several rare forms of seizure disorder and the cases (Treiman and Treiman, 2001). The difference majority of genes are involved with ion homeostasis in concordance between MZ and DZ twins is so ev- leading to the notion that many seizure disorders ident, and recent genetic studies revealed some re- are caused by “ion channelopathies” (Table 1). sponsible genes in certain idiopathic epilepsy syn- Other forms of familial epilepsy are caused by mu- dromes. The focus of genetic investigation in the tations in non-ion channel genes (Table 2). This epilepsies is the identification of genetic defects article reviews recent progress made in molecular genetics of epilepsy and perspectives of molecular *To whom correspondence should be addressed. study of epilepsy. TEL: 032-890-3418, FAX: 032-890-3864 e-mail: [email protected] 72 C-H. Yun & B.S. Jeon Table 1. Ion channel-related genetic defects in human epilepsy Syndrome Chromosomal region Gene Gene function ADNFLE type 1 20q13.2-q13.3 CHRNA4 α4 subunit of nicotinic Ach receptor (Steinlein et al., 1995 and 1997; Hirose et al., 1999) ADNFLE type 2 15q24 ? Nicotinic Ach receptor subunit7 ADNFLE type 3 1 (pericentromeric region) CHRNB2 β2 subunit of nicotinic Ach receptor (Fusco et al., 2000; Phillips et al., 2001) BNFC 20q13 KCNQ2 Potassium channel subunit (Singh et al., 1998) 8q KCNQ3 Potassium channel subunit (Charlier et al., 1998) 6q14 KCNQ5 Potassium channel subunit (Kananura et al., 2000) FS FEB1 8q13-q21 ? ? (Wallace et al., 1996) FEB2 19q13 ? ? (Johnson et al., 1997) FEB3 2q23-q24 ? ? (Peiffer et al., 1999) FEB4 5q14-q15 ? ? (Matsushima et al., 2002) GEFS FEB1+ 19q13.1 SCN1B Sodium channel β1 subunit (Wallace et al., 1998) FEB2+ 2q21-q33 SCN1A Sodium channel α1 subunit (Wallace et al., 2001) FEB3+ 5q34 GABRG2 γ2 subunit of GABA receptor (Baulac et al., 2001) FEB4+ 2q24-q33 SCN2A Sodium channel 2 subunit (Sugawara et al., 2001a) FS+CAE 5q34 GABRG2 γ2 subunit of GABA receptor (Wallace et al., 2001) SMEI SMEI 2q24 SCN1A Sodium channel α1 subunit (Claes et al., 2001) FS+ including SMEI 5q34 GARG2 γ2 subunit of GABA receptor (Harkin et al., 2002) JME 6p11-p12 LMPBI Lysosomal membrane protein (Suzuki et al., 2001) 15q CHRNA7? α7 nicotinic acetylcholine receptor (Elmslie et al., 1997) 5q32-q35 GABRA1 α1 subunit of GABA receptor (Cossette et al., 2002) ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; BNFC, benign neonatal familial convulsion; FS, febrile seizure; GEFS, generalized epilepsy with febrile seizure; CAE, childhood absence epilepsy; SMEI, severe myoclonic epilepsy of infancy; JME, juvenile myoclonic epilepsy. Table 2. Some non-ion channel-related genes cloned in human epilepsy Syndrome Chromosomal region Gene Gene function PME Unverricht-Lundborg type 21q23 EPM1 Cystatin B (Virtaneva et al., 1997) Lafora's disease 6q24 EPM2 Laforin, protein tyrosine phosphatase (Minassian et al., 1998) ADPE with auditory feature 1q LGI1 Leucine-rich, glioma-inactivated 1 protein (tumor suppressor?) (Fertig et al., 2003) Autosomal dominant nocturnal frontal lobe disorder inherited as an autosomal dominant trait epilepsy with high penetrance. Using genetic linkage analy- Autosomal dominant nocturnal frontal lobe ep- ses, the responsible gene has been mapped to ilepsy (ADNFLE) was first reported as a new clin- chromosome 20q13.2 (Phillips et al., 1995). Subse- ical entity of epilepsy in 1994. ADNFLE is charac- quent linkage studies in families with ADNFLE terized by clusters of a brief seizure with frontal showed that the candidate genes in some families lobe semiology during non-rapid eye movement with ADNFLE reside on chromosomes 15q24 and 1 (NREM) sleep, and is often misdiagnosed as night- (Steinlein et al., 1997; Phillips et al., 1998 and 2001; mare or parasomnia (Scheffer et al., 1995). Onset Hirose et al., 1999; Fusco et al., 2000). ADNFLE usually occurs in mid-childhood. Responsiveness to with genetic locus on chromosomes 20q13.2, 15q24 antiepileptic drugs such as carbamazepine is excel- and 1 are referred to as ADNFLE type 1, 2, and 3, lent except some patients. ADNFLE is a monogenic respectively. Mutations in the neuronal acetylcholine Genetics in Epilepsy 73 receptor α4 subunit (CHRNA4) gene CHRNA4, and of CHRNB2, representing apparent opposite chan- β2 subunit (CHRNB2) gene CHRNB2, have been nel function, could also be considered as another found in ADNFLE type 1 and 3, respectively. pathophysiological mechanism of ADNFLE. Thus, CHRNA4 is a subunit of neuronal nicotinic acetyl- further studies are necessary to determine the mo- choline receptor (nAChR) in the brain. CHRNA4 is lecular pathogenesis of epilepsy of ADNFLE due to assembled into a hetero-pentamer that functions as abnormalities of nAChR (Forman et al., 1996). a nAChR. Since CHRNA4 is expressed widely in the brain and forms nAChR mainly with CHRNB2, Benign familial neonatal convulsion (α4)2(β2)3 is considered as the dominant subtype Benign familial neonatal convulsions (BFNC) is of nAChR in the brain. As a structure of the α- an autosomal dominant disorder with neonatal on- subunit of AChR, CHRNA4 is typically equipped set and high penetrance, and is characterized by with a binding site for acetylcholine at the C termi- clusters of generalized and partial seizures, and nus and spans the plasma membrane four times. remits spontaneously within 8 mo. However, the For ADNFLE type 1, a missense mutation (c.839C . incidence of subsequent epilepsy later in life is T; S280F), an insertional mutation of CHRNA4 about 11% (Plouin, 1997). BFNC has been linked (c.873874insGCT; L301302) and a point mutation of to mutations in three K-channel genes, KCNQ2 on CHRNA4 (c.851C . T; S284L) in CHRNA4 has been chromosome 20 (BFNC1), KCNQ3 (BFNC2) on reported (Steinlein et al., 1997; Phillips et al., 1998; chromosome 8, and KCNQ5 (BFNC3) on chromo- Hirose et al., 1999). Electrophysiological studies of some 6 (Charlier, et al., 1998; Singh et al., 1998; AChR reveal that both mutations seem to lead to Kananura et al., 2000). Abnormalities of both KCNQ2 loss-of-function of nAChR resulting reduced calcium and KCNQ3 lead to dysfunction of the M-current, a permeability of the mutant nAChR (Steinlein, 1998; slowly activating and deactivating potassium con- Matsushima et al., 2002). Dominant inheritance in ductance critical to determining the subthreshold ADNFLE resulting from these loss-of-function muta- electrical excitability of neurons (Wang et al., 1998). tions seems to be explained as a dominant neg- KCNQ2 and KCNQ3 synergistically contribute to ative effect. For ADNFLE type 3, two missense mu- formation of the native M current. Deficient KCNQ2 tations (c.859G . C; V287L, c.859G . A; V287M) of or KCNQ3 does not necessarily abolish M-current CHRNB2, which is mapped to chromosome 1p21, but reduces it by 30%. Nominal reduction of M- have been identified (Fusco et al., 2000; Phillips et current, therefore, can undermine the inhibitory sys- al., 2001). Interestingly, the missense mutations tem of the CNS in the newborn. identified in CHRNB2 are also located at the M2 Schwake et al. (2002) reported that the increased region of CHRNB2 corresponding to mutations of currents of heterometric KCNQ2 and KCNQ3 chan- CHRNA4 described above. In contrast to the elect- nels were due to an increased expression of active rophysiological characteristics of CHRNA4 muta- channels on the plasma membrane. The C-terminus tions, however, V287L leads to slow deactivation of KCNQ2 was found to play an important role in while V287M mutation confers higher affinity to ACh such efficient surface expression. Most mutations of on the receptor. These mutations are thus consid- KCNQ2 so far found in BFNC1 are located in the ered to lead to ‘gain-of-function’ although the phe- C-terminus, some of which have been demon- notype of ADNFLE resulting from these mutations, strated to hamper the surface expression of hetero- type 3, is indistinguishable from ADNFLE type 1, metric channels with KCNQ3 and thereby reduce resulting from CHRNA4 mutations. Since nAChR is K-current.
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