Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

被引:139
作者
Rhodes, TH
Lossin, C
Vanoye, CG
Wang, DW
George, AL
机构
[1] Vanderbilt Univ, Div Genet Med, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA
关键词
seizure; generalized epilepsy with febrile seizures plus SCN1A; electrophysiology;
D O I
10.1073/pnas.0402482101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha(1) subunit (Na(v)1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent, noninactivating channel activity resembling the pattern of channel dysfunction observed for alleles associated with generalized epilepsy with febrile seizures plus. Our data provide evidence for a range of SCN1A functional abnormalities in SMEI, including gain-of-function defects that were not anticipated in this disorder. Our results further indicate that a complex relationship exists between phenotype and aberrant sodium channel function in these inherited epilepsies.
引用
收藏
页码:11147 / 11152
页数:6
相关论文
共 34 条
[1]   Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation [J].
Abou-Khalil, B ;
Ge, Q ;
Desai, R ;
Ryther, R ;
Bazyk, A ;
Bailey, R ;
Haines, JL ;
Sutcliffe, JS ;
George, AL .
NEUROLOGY, 2001, 57 (12) :2265-2272
[2]   Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man [J].
Alekov, AK ;
Rahman, M ;
Mitrovic, N ;
Lehmann-Horn, F ;
Lerche, H .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 13 (11) :2171-2176
[3]   A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro [J].
Alekov, AK ;
Rahman, MM ;
Mitrovic, N ;
Lehmann-Horn, F ;
Lerche, H .
JOURNAL OF PHYSIOLOGY-LONDON, 2000, 529 (03) :533-539
[4]   A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy [J].
Audenaert, D ;
Claes, L ;
Ceulemans, B ;
Löfgren, A ;
Van Broeckhoven, C ;
De Jonghe, P .
NEUROLOGY, 2003, 61 (06) :854-856
[5]   First genetic evidence of GABAA receptor dysfunction in epilepsy:: a mutation in the γ2-subunit gene [J].
Baulac, S ;
Huberfeld, G ;
Gourfinkel-An, I ;
Mitropoulou, G ;
Beranger, A ;
Prud'homme, JF ;
Baulac, M ;
Brice, A ;
Bruzzone, R ;
LeGuern, E .
NATURE GENETICS, 2001, 28 (01) :46-48
[6]   De Novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy [J].
Claes, L ;
Ceulemans, B ;
Audenaert, D ;
Smets, K ;
Löfgren, A ;
Del-Favero, J ;
Ala-Mello, S ;
Basel-Vanagaite, L ;
Plecko, B ;
Raskin, S ;
Thiry, P ;
Wolf, NI ;
Van Broeckhoven, C ;
De Jonghe, P .
HUMAN MUTATION, 2003, 21 (06) :615-621
[7]   De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy [J].
Claes, L ;
Del-Favero, J ;
Ceulemans, B ;
Lagae, L ;
Van Broeckhoven, C ;
De Jonghe, P .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (06) :1327-1332
[8]   Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS) [J].
Cossette, P ;
Loukas, A ;
Lafrenière, RG ;
Rochefort, D ;
Harvey-Girard, E ;
Ragsdale, DS ;
Dunn, RJ ;
Rouleau, GA .
EPILEPSY RESEARCH, 2003, 53 (1-2) :107-117
[9]  
Dravet Charlotte, 1992, P75
[10]   Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2 [J].
Escayg, A ;
MacDonald, BT ;
Meisler, MH ;
Baulac, S ;
Huberfeld, G ;
An-Gourfinkel, I ;
Brice, A ;
LeGuern, E ;
Moulard, B ;
Chaigne, D ;
Buresi, C ;
Malafosse, A .
NATURE GENETICS, 2000, 24 (04) :343-345