Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity.
METHODS
Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships.


RESULTS
Mutations in SMEI occurred more frequently in the "pore" regions of SCN1A than did those in GEFS+. These SMEI mutations in the "pore" regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient.


CONCLUSIONS
There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.
Kanai
K
K
Department of Neuropsychiatry, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. VZR03355@nifty.ne.jp
Hirose
S
S
Oguni
H
H
Fukuma
G
G
Shirasaka
Y
Y
Miyajima
T
T
Wada
K
K
Iwasa
H
H
Yasumoto
S
S
Matsuo
M
M
Ito
M
M
Mitsudome
A
A
Kaneko
S
S
D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001259:Ataxia / Q000235:genetics; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D017136:Ion Transport / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D003294:Seizures, Febrile / Q000235:genetics*; D016415:Sequence Alignment; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels