Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort Of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin-1A

Mutations in the KCNQ2 and KCNQ3 genes encoding for K(v)7.2 (KCNQ2; Q2) and K(v)7.3 (KCNQ3; Q3) voltage-dependent K+ channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named KCNQ2 encephalopathy. In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. Hum Mutat 35:356-367, 2014. (C) 2013 Wiley Periodicals, Inc.