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Novel KCNQ 2 and KCNQ 3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin‐1 A
Author(s) -
Soldovieri Maria Virginia,
BoutryKryza Nadia,
Milh Mathieu,
Doummar Diane,
Heron Benedicte,
Bourel Emilie,
Ambrosino Paolo,
Miceli Francesco,
Maria Michela,
Dorison Nathalie,
Auvin Stephane,
Echenne Bernard,
Oertel Julie,
Riquet Audrey,
Lambert Laetitia,
Gerard Marion,
Roubergue Anne,
Calender Alain,
Mignot Cyril,
Taglialatela Maurizio,
Lesca Gaetan
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22500
Subject(s) - biology , epilepsy , genetics , homomeric , phenotype , mutation , genetic heterogeneity , gene , neuroscience , protein subunit
Mutations in the KCNQ 2 and KCNQ 3 genes encoding for K v 7.2 ( KCNQ 2; Q 2) and K v 7.3 ( KCNQ 3; Q 3) voltage‐dependent K + channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy ( BFNE ), KCNQ 2 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 ( O htahara syndrome), and distinct neuroradiological features, a condition that was named “ KCNQ 2 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 KCNQ 2 , including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ 3 . Most of these mutations were novel, except for four KCNQ 2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ 2 and/or KCNQ 3 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‐1 A , highlighting a novel pathogenetic mechanism for KCNQ 2‐related epilepsies.