De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.
BACKGROUND
Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.


METHODS
We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations.


RESULTS
We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation.


CONCLUSIONS
The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama, Japan.
I
I
Ogiwara
K
K
Ito
Y
Y
Sawaishi
H
H
Osaka
E
E
Mazaki
I
I
Inoue
M
M
Montal
T
T
Hashikawa
T
T
Shike
T
T
Fujiwara
Y
Y
Inoue
M
M
Kaneda
K
K
Yamakawa
D000595:Amino Acid Sequence; D002460:Cell Line; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology*; D017809:Fatal Outcome; D005260:Female; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000166:cytology; D008297:Male; D020125:Mutation, Missense; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D013036:Spasms, Infantile / Q000235:genetics / Q000503:physiopathology; D014162:Transfection; D055815:Young Adult
D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; D015222:Sodium Channels