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The Journal of Neuroscience, October 10, 2007, 27(41):11037-11046; doi:10.1523/JNEUROSCI.3515-07.2007

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Neurobiology of Disease
Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺ Channel Mutant

Raffaella Rusconi,^1 * Paolo Scalmani,^1 * Rita Restano Cassulini,² Giulia Giunti,¹ Antonio Gambardella,^3,4 Silvana Franceschetti,¹ Grazia Annesi,⁴ Enzo Wanke,² and Massimo Mantegazza¹

¹Department of Neurophysiopathology, Besta Neurological Institute, 20133 Milan, Italy, ²Department of Biotechnology and Biosciences, Milano-Bicocca University, 20126 Milan, Italy, ³Institute of Neurology, Magna Graecia University, 88100 Catanzaro, Italy, and ⁴Institute of Neurological Sciences, Consiglio Nazionale delle Ricerche, 87050 Mangone, Italy

Correspondence should be addressed to either of the following: Dr. Massimo Mantegazza, Department of Neurophysiopathology, Istituto Neurologico Besta, Via Celoria 11, 20133 Milano, Italy, Email: mmantegazza{at}istituto-besta.it; or Prof. Enzo Wanke, Department of Biology and Biotechnology, Università di Milano-Bicocca, Piazza della Scienza, 20126 Milan, Italy, Email: enzo.wanke{at}unimib.it

Familial epilepsies are often caused by mutations of voltage-gated Na⁺ channels, but correlation genotype–phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na_v1.1 (SCN1A) Na⁺ channel subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na⁺ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein–protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.

Key words: sodium; current; epilepsy; excitability; trafficking; GEFS+; SMEI; seizure; SCN1A

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Received March 3, 2007; revised Aug. 14, 2007; accepted Aug. 15, 2007.

Correspondence should be addressed to either of the following: Dr. Massimo Mantegazza, Department of Neurophysiopathology, Istituto Neurologico Besta, Via Celoria 11, 20133 Milano, Italy, Email: mmantegazza{at}istituto-besta.it; or Prof. Enzo Wanke, Department of Biology and Biotechnology, Università di Milano-Bicocca, Piazza della Scienza, 20126 Milan, Italy, Email: enzo.wanke{at}unimib.it

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