TY - JOUR
T1 - Novel SCN3A variants associated with focal epilepsy in children
AU - Vanoye, Carlos G.
AU - Gurnett, Christina A.
AU - Holland, Katherine D.
AU - George, Alfred L.
AU - Kearney, Jennifer A.
N1 - Funding Information:
This work was supported by NIH grants NS032387 (A.L.G.) and NS053792 (J.A.K.). The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
PY - 2014/2
Y1 - 2014/2
N2 - Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
AB - Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
KW - Epilepsy
KW - Persistent current
KW - Ramp currents
KW - SCN3A
KW - Sodium channel
UR - http://www.scopus.com/inward/record.url?scp=84887358909&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.10.015
DO - 10.1016/j.nbd.2013.10.015
M3 - Article
C2 - 24157691
AN - SCOPUS:84887358909
SN - 0969-9961
VL - 62
SP - 313
EP - 322
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -