Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal seizures (BFNS), a dominantly-inherited, highly penetrant early-onset epilepsy syndrome. BFNS causes frequent seizures during the neonatal period, but after seizures remit, affected individuals develop normally. However, compelling evidence now implicates a subset of KCNQ2 mutations in persistent and disabling CNS and neuromuscular diseases. KCNQ2 pedigrees exhibit painful myokymia (without seizures), myokymia after neonatal seizures, epilepsy after the neonatal period, and epilepsy with significant intellectual disability. Most importantly, a recent Euro-Australian collaborative study describes de novo KCNQ2 mutations in 10% of cases (8/80) of severe, sporadic, early- onset epileptic encephalopathy (EEE). As disclosed in this renewal application, our lab has ascertained 6 additional individuals from North America with EEE bearing novel KCNQ2 mutations. Although factors such as genetic background and epigenetics may influence these phenotypes, our analysis suggests mechanisms whereby the de novo KCNQ2 mutations in EEE patients may act as potent dominant-negatives, suppressing activity up to 94% (16-fold), whereas known BFNS mutations are known to generally reduce activity by 20-50% (2-fold or less). Here, we propose to define the developmental time course for the arrival of KCNQ2 and KCNQ3-containing channels at the axonal membrane of neurons in the hippocampal formation and the somatosensory and motor neocortex, assayed in normal rodents, KCNQ2 mutant mice, and human tissue. In parallel with anatomical study, we will also analyze the function of hippocampal and neocortical axonal KCNQ channels at the subcellular, cellular, and behavioral level through in vitro analysis, patch clamp recording, and transgenic animal models. Finally, we will analyze and compare the efficacy two KCNQ opener drugs which differ in potency, maximal efficacy and subunit specificity, to activate channels in vitro and terminate seizures in vivo.

Public Health Relevance

Proteins called ion channels create the electrical signals in the brain that are the physical basis for activities such as thinking, sensation, and body movement. Ion channel variants can be responsible for several types of epilepsy which begin early after birth and are sometime followed by severe developmental delay. This study will analyze how variation in the ion channel called KCNQ2 cause such symptoms and test new strategies for treating and curing affected individuals, by using molecular biology, and studies of cells in culture and mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049119-08
Application #
8609604
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Whittemore, Vicky R
Project Start
2004-07-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
$338,921
Indirect Cost
$122,358
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lopez, A Y; Wang, X; Xu, M et al. (2017) Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Mol Psychiatry 22:1464-1472
Mulkey, Sarah B; Ben-Zeev, Bruria; Nicolai, Joost et al. (2017) Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H. Epilepsia 58:436-445
Millichap, John J; Miceli, Francesco; De Maria, Michela et al. (2017) Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia 58:e10-e15
Millichap, John J; Park, Kristen L; Tsuchida, Tammy et al. (2016) KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2:e96
Xu, Mingxuan; Cooper, Edward C (2015) An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels. J Biol Chem 290:16619-32
Martinello, Katiuscia; Huang, Zhuo; Lujan, Rafael et al. (2015) Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells. Neuron 85:346-63
Ho, Tammy Szu-Yu; Zollinger, Daniel R; Chang, Kae-Jiun et al. (2014) A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier. Nat Neurosci 17:1664-72
Kole, Maarten H P; Cooper, Edward C (2014) Axonal Kv7.2/7.3 channels: caught in the act. Channels (Austin) 8:288-9
Battefeld, Arne; Tran, Baouyen T; Gavrilis, Jason et al. (2014) Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons. J Neurosci 34:3719-32
Chang, Kae-Jiun; Zollinger, Daniel R; Susuki, Keiichiro et al. (2014) Glial ankyrins facilitate paranodal axoglial junction assembly. Nat Neurosci 17:1673-81

Showing the most recent 10 out of 18 publications