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NEUROLOGY 2004;63:57-65
© 2004 American Academy of Neurology

A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation

R. Borgatti, MD, C. Zucca, MD, A. Cavallini, MD, M. Ferrario, PhD, C. Panzeri, BS, P. Castaldo, PhD, M. V. Soldovieri, BS, C. Baschirotto, BS, N. Bresolin, MD, B. Dalla Bernardina, MD, M. Taglialatela, MD PhD and M. T. Bassi, PhD

From the IRCCS "Eugenio Medea" (Drs. Borgatti, Zucca, Cavallini, Ferrario, Bresolin, and Bassi, and C. Panzeri and C. Baschirotto), Bosisio Parini (Lecco); Division of Pharmacology (Drs. Castaldo and Taglialatela and M.V. Soldovieri), Department of Neuroscience, University of Napoli Federico II, Napoli; IRCCS Ospedale Maggiore Policlinico (Dr. Bresolin), Milan, "Centro Dino Ferrari," Department of Neurology, University of Milan; and Division of Neuropediatrics Policlinico "Borgo Roma" (Dr. Dalla Bernardina), Verona, Italy.

Address correspondence and reprint requests to Dr. Renato Borgatti, Divisione di Neuroriabilitazione 1, I.R.C.C.S. "Eugenio Medea," La Nostra Famiglia, Via Don Luigi Monza, 20, 23842 Bosisio Parini (Lecco), Italy; e-mail: borgatti{at}bp.lnf.it

Background: Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation.

Methods: The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation.

Results: All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression.

Conclusion: The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.

Received September 15, 2003. Accepted in final form March 8, 2004.




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