TY - JOUR
T1 - Molecular basis of an inherited epilepsy
AU - Lossin, Christoph
AU - Wang, Dao W.
AU - Rhodes, Thomas H.
AU - Vanoye, Carlos G.
AU - George, Alfred L.
N1 - Funding Information:
We thank Dr. Naomasa Makita for the generous gift of the pCD8-IRES-hβ1 plasmid and Megan Olarte for DNA sequencing. We also are grateful to Dr. Robert MacDonald for critical reading of the manuscript. This project was supported by NIH grant NS3287 (A.L.G.) and by a predoctoral fellowship award from the Epilepsy Foundation (C.L.). This project was also funded by the Epilepsy Foundation through the generosity of the Kathy Holden Genetic Research Fund and supported by a grant from the Roland and Ruby Holden Foundation on behalf of Ronald and Arlene Holden.
PY - 2002
Y1 - 2002
N2 - Epilepsy is a common neurological condition that reflects neuronal hyperexcitability arising from largely unknown cellular and molecular mechanisms. In generalized epilepsy with febrile seizures plus, an autosomal dominant epilepsy syndrome, mutations in three genes coding for voltage-gated sodium channel α or β1 subunits (SCN1A, SCN2A, SCN1B) and one GABA receptor subunit gene (GABRG2) have been identified. Here, we characterize the functional effects of three mutations in the human neuronal sodium channel α subunit SCN1A by heterologous expression with its known accessory subunits, β1 and β2, in cultured mammalian cells. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality will likely enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for this inherited human epilepsy.
AB - Epilepsy is a common neurological condition that reflects neuronal hyperexcitability arising from largely unknown cellular and molecular mechanisms. In generalized epilepsy with febrile seizures plus, an autosomal dominant epilepsy syndrome, mutations in three genes coding for voltage-gated sodium channel α or β1 subunits (SCN1A, SCN2A, SCN1B) and one GABA receptor subunit gene (GABRG2) have been identified. Here, we characterize the functional effects of three mutations in the human neuronal sodium channel α subunit SCN1A by heterologous expression with its known accessory subunits, β1 and β2, in cultured mammalian cells. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality will likely enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for this inherited human epilepsy.
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U2 - 10.1016/S0896-6273(02)00714-6
DO - 10.1016/S0896-6273(02)00714-6
M3 - Article
C2 - 12086636
AN - SCOPUS:0037071896
VL - 34
SP - 877
EP - 884
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 6
M1 - S0896-6273(02)00714-6
ER -