KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum.

Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant generalized epilepsy of the newborn infant. Seizures occur repeatedly in the first days of life and remit by approximately 4 months of age. Previously our laboratory cloned two novel potassium channel genes, KCNQ2 and KCNQ3, and showed that they are mutated in patients with BFNC. In this report, we characterize the breakpoints of a previously reported interstitial deletion in the KCNQ2 gene and show that only KCNQ2 is deleted. We identify 11 novel mutations in KCNQ2 and one novel mutation in the KCNQ3 potassium channel genes. In one family, the phenotype extends beyond neonatal seizures and includes rolandic seizures, and a subset of families has onset of seizures in infancy. In the Xenopus oocyte expression system, we characterize five KCNQ2 and one KCNQ3 disease-causing mutations. These mutations cause a variable loss of function, and selective effects on the biophysical properties of KCNQ2/KCNQ3 heteromultimeric channels. We report here the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment.

Singh NA ，Westenskow P ，Charlier C ，Pappas C ，Leslie J ，Dillon J ，Anderson VE ，Sanguinetti MC ，Leppert MF ，BFNC Physician Consortium ... -  《BRAIN》

Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium channel: a novel mutation in a large Czech pedigree with benign neonatal convulsions or other epileptic phenotypes.

Benign neonatal familial convulsions (BNFCs) represent a rare epileptic disorder with autosomal dominant mode of inheritance. To date, two voltage-gated potassium (K+) channel genes, KCNQ2 and KCNQ3, have been identified in typical BNFC families. The study of new pedigrees may help detect new mutations and define genotype-phenotype correlations. A large Czech family was detected in which BNFC was inherited together with a broad range of various nonneonatal epileptic phenotypes. Genetic linkage study and direct mutation analysis were performed to find the disease-causing mutation. In seven patients with BNFCs and no recurrence of seizures, a novel two-base-pair deletion (1369del2) was identified within the coding sequence of the KCNQ2 gene. The mutation led to a putative protein that lacked nearly all its carboxyl terminus part, which plays a critical role for the accurate expression of the functional K+ channels. Three patients with generalized tonic-clonic seizures (GTCSs), all without any history of BNFCs, also displayed 1369del2. Three other patients with other idiopathic epileptic phenotypes did not have the mutation. A novel 2-bp deletion within the coding sequence of the potassium channel KCNQ2 gene was detected in patients from a large and heterogeneous family with BNFCs or non-BNFC seizures.

Pereira S ，Roll P ，Krizova J ，Genton P ，Brazdil M ，Kuba R ，Cau P ，Rektor I ，Szepetowski P ... -  《EPILEPSIA》

A novel mutation in KCNQ2 gene causes benign familial neonatal convulsions in a Chinese family.

Benign familial neonatal convulsions (BFNC) are a rare autosomal dominant inherited epilepsy syndrome. Two voltage-gated potassium channel genes, KCNQ2 on chromosome 20q13.3 and KCNQ3 on chromosome 8q24, have been identified as the genes responsible for benign familial neonatal convulsions. By linkage analysis and mutation analysis of KCNQ2 gene, we found a novel frameshift mutation of KCNQ2 gene, 1931delG, in a large Chinese family with benign familial neonatal convulsions. This mutation is located in the C-terminus of KCNQ2, in codon 644 predicting the replacement of the last 201 amino acids with a stretch of 257 amino acids showing a completely different sequence. An unusual clinical feature of this family is that the seizures of every patient did not remit until 12 to 18 months. This is the first report of KCNQ2 gene mutation in China.

Tang B ，Li H ，Xia K ，Jiang H ，Pan Q ，Shen L ，Long Z ，Zhao G ，Cai F ... -  《JOURNAL OF THE NEUROLOGICAL SCIENCES》

Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy.

Schroeder BC ，Kubisch C ，Stein V ，Jentsch TJ ... -  《NATURE》

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes.

Neubauer BA ，Waldegger S ，Heinzinger J ，Hahn A ，Kurlemann G ，Fiedler B ，Eberhard F ，Muhle H ，Stephani U ，Garkisch S ，Eeg-Olofsson O ，Müller U ，Sander T ... -  《-》