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Sarenur Gokben, Huseyin Onay, Sanem Yilmaz, Tahir Atik, Gul Serdaroglu, Hande Tekin, Ferda Ozkinay
We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one...
October 12, 2016: Acta Neurologica Belgica
Steven R Brant, David T Okou, Claire L Simpson, David J Cutler, Talin Haritunians, Jonathan P Bradfield, Pankaj Chopra, Jarod Prince, Ferdouse Begum, Archana Kumar, Chengrui Huang, Suresh Venkateswaran, Lisa W Datta, Zhi Wei, Kelly Thomas, Lisa J Herrinton, Jan-Micheal A Klapproth, Antonio J Quiros, Jenifer Seminerio, Zhenqiu Liu, Jonathan S Alexander, Robert N Baldassano, Sharon Dudley-Brown, Raymond K Cross, Themistocles Dassopoulos, Lee A Denson, Tanvi A Dhere, Gerald W Dryden, John S Hanson, Jason K Hou, Sunny Z Hussain, Jeffrey S Hyams, Kim L Isaacs, Howard Kader, Michael D Kappelman, Jeffry Katz, Richard Kellermayer, Barbara S Kirschner, John F Kuemmerle, John H Kwon, Mark Lazarev, Ellen Li, David Mack, Peter Mannon, Dedrick E Moulton, Rodney D Newberry, Bankole O Osuntokun, Ashish S Patel, Shehzad A Saeed, Stephan R Targan, John F Valentine, Ming-Hsi Wang, Martin Zonca, John D Rioux, Richard H Duerr, Mark S Silverberg, Judy H Cho, Hakon Hakonarson, Michael E Zwick, Dermot P B McGovern, Subra Kugathasan
BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified [IBD-U]) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database)...
September 28, 2016: Gastroenterology
Ruchi Malik, Pakhuri Mehta, Shubham Srivastava, Bhanwar Singh Choudhary, Manish Sharma
Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity...
September 8, 2016: Journal of Receptor and Signal Transduction Research
John J Millichap, Kristen L Park, Tammy Tsuchida, Bruria Ben-Zeev, Lionel Carmant, Robert Flamini, Nishtha Joshi, Paul M Levisohn, Eric Marsh, Srishti Nangia, Vinodh Narayanan, Xilma R Ortiz-Gonzalez, Marc C Patterson, Phillip L Pearl, Brenda Porter, Keri Ramsey, Emily L McGinnis, Maurizio Taglialatela, Molly Tracy, Baouyen Tran, Charu Venkatesan, Sarah Weckhuysen, Edward C Cooper
OBJECTIVE: To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. METHODS: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients. RESULTS: The mean seizure onset age was 1...
October 2016: Neurology. Genetics
Ruud Zwart, Hannah Reed, Sophie Clarke, Emanuele Sher
Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-currents. We found that this cross-talk can be reconstituted in Xenopus oocytes by co-transfection of human recombinant muscarinic M1 receptors and KCNQ2/3 potassium channels. Application of the muscarinic acetylcholine receptor agonist Oxotremorine-methiodide (Oxo-M) between voltage pulses to activate KCNQ2/3 channels caused inhibition of the subsequent KCNQ2/3 responses...
August 31, 2016: European Journal of Pharmacology
Montesclaros Hortigüela, Ana Fernández-Marmiesse, Verónica Cantarín, Sofía Gouveia, Juan J García-Peñas, Carmen Fons, Judith Armstrong, Desirée Barrios, Felícitas Díaz-Flores, Pilar Tirado, María L Couce, Luis G Gutiérrez-Solana
The KCNQ2 gene codifies a subunit of the voltage-gated potassium M channel underlying the neuronal M-current. Classically, mutations in this gene have been associated with benign familial neonatal seizures, however, in recent years KCNQ2 mutations have been reported associated to early-onset epileptic encephalopathy. In this work, detailed familiar, clinical and genetic data were collected for 13 KCNQ2-positive patients revealed among a cohort of 80 epileptic pediatric probands from Spain who were analyzed through a targeted next-generation sequencing assay for 155 epilepsy-associated genes...
August 18, 2016: Journal of Human Genetics
Alice W Wang, Runying Yang, Harley T Kurata
Retigabine is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. Retigabine exhibits little specificity between KCNQ2-5, due to conservation of a Trp residue in the pore domain that binds to the drug. The retigabine analog ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, roughly two-fold enhancement of peak current, and pronounced subtype specificity for KCNQ2 over KCNQ3...
August 9, 2016: Journal of Physiology
Hyun-Ji Kim, Myong-Ho Jeong, Kyung-Ran Kim, Chang-Yun Jung, Seul-Yi Lee, Hanna Kim, Jewoo Koh, Tuan Anh Vuong, Seungmoon Jung, Hyunwoo Yang, Su-Kyung Park, Dahee Choi, Sung Hun Kim, KyeongJin Kang, Jong-Woo Sohn, Joo Min Park, Daejong Jeon, Seung-Hoi Koo, Won-Kyung Ho, Jong-Sun Kang, Seong-Tae Kim, Hana Cho
KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca(2+)/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities...
2016: ELife
Najing Zhou, Sha Huang, Li Li, Dongyang Huang, Yunli Yan, Xiaona Du, Hailin Zhang
Membrane potential shift driven by electrical activity is critical in determining the cell fate of proliferation or differentiation. As such, the ion channels that underlie the membrane electrical activity play an important role in cell proliferation/differentiation. KV7/KCNQ potassium channels are critical in determining the resting membrane potentials in many neuronal cells. However, the role of these channels in cell differentiation is not well studied. In the present study, we used PC12 cells as well as primary cultured rat cortical neurons to study the role and mechanism of KV7/KCNQ in neuronal differentiation...
October 1, 2016: Neuroscience
Gucan Dai, Haijie Yu, Martin Kruse, Alexis Traynor-Kaplan, Bertil Hille
Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na(+)/myo-inositol cotransporter (SMIT1) and myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons...
June 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jérôme Devaux, Affef Abidi, Agathe Roubertie, Florence Molinari, Hélène Becq, Caroline Lacoste, Laurent Villard, Mathieu Milh, Laurent Aniksztejn
Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2(V175L) ) found in a patient presenting EOEE. We observed that the mutation produced a 25-40 mV hyperpolarizing shift of the conductance-voltage relationship of both the homomeric Kv7...
May 2016: Epilepsia
Manoj Kumar, Nicholas Reed, Ruiting Liu, Elias Aizenman, Peter Wipf, Thanos Tzounopoulos
KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain, and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an anticonvulsant approved by the U.S. Food and Drug Administration...
June 2016: Molecular Pharmacology
M Milh, P Cacciagli, C Ravix, C Badens, A Lépine, N Villeneuve, L Villard
Early onset epileptic encephalopathies (EOEE) are heterogeneous group of severe epilepsies that still need to be better defined and characterized. On a genetic point of view, several dozen of genes have been associated with EOEE, and to date, it is difficult to find a common mechanism to explain EOEE. In this short review, we show that two mains genes are involved in EOEE: STXBP1 and KCNQ2. Focusing on KCNQ2 related EOEE, we show that a relatively similar phenotype can be related to various consequences of mutations on a single gene...
March 2016: Revue Neurologique
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
Kwang S Kim, Kevin M Duignan, Joanna M Hawryluk, Heun Soh, Anastasios V Tzingounis
The slow afterhyperpolarization (sAHP) is a calcium-activated potassium conductance with critical roles in multiple physiological processes. Pharmacological and genetic data suggest that KCNQ channels partly mediate the sAHP. However, these channels are not typically open within the observed voltage range of the sAHP. Recent work has shown that the sAHP is gated by increased PIP2 levels, which are generated downstream of calcium binding by neuronal calcium sensors such as hippocalcin. Here, we examined whether changes in PIP2 levels could shift the voltage-activation range of KCNQ channels...
March 8, 2016: Biophysical Journal
Yukiko Ihara, Yuko Tomonoh, Masanobu Deshimaru, Bo Zhang, Taku Uchida, Atsushi Ishii, Shinichi Hirose
The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates...
2016: PloS One
Zaid Afawi, Karen L Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y Neufeld, Katherine L Helbig, Hadassa Goldberg-Stern, Adel J Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H Wallace, Marie Mangelsdorf, James N MacPherson, Gemma L Carvill, Heather C Mefford, Graeme D Jackson, Ingrid E Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E Heron, Mark Corbett, John C Mulley, Leanne M Dibbens, Amos D Korczyn, Samuel F Berkovic
OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate...
February 23, 2016: Neurology
Katherine L Helbig, Kelly D Farwell Hagman, Deepali N Shinde, Cameron Mroske, Zöe Powis, Shuwei Li, Sha Tang, Ingo Helbig
PURPOSE: To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy. METHODS: In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis. RESULTS: Positive/likely positive results were identified in 112/293 (38...
September 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Giovanna Marchese, Francesca Rizzo, Anna Guacci, Alessandro Weisz, Giangennaro Coppola
No abstract text is available yet for this article.
May 2016: Neurological Sciences
Sebastian Schütze, Ian J Orozco, Thomas J Jentsch
M-current-mediating KCNQ (Kv7) channels play an important role in regulating the excitability of neuronal cells, as highlighted by mutations in Kcnq2 and Kcnq3 that underlie certain forms of epilepsy. In addition to their expression in brain, KCNQ2 and -3 are also found in the somatosensory system. We have now detected both KCNQ2 and KCNQ3 in a subset of dorsal root ganglia neurons that correspond to D-hair Aδ-fibers and demonstrate KCNQ3 expression in peripheral nerve endings of cutaneous D-hair follicles...
March 11, 2016: Journal of Biological Chemistry
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