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https://www.readbyqxmd.com/read/28602030/variable-expressivity-of-a-likely-pathogenic-variant-in-kcnq2-in-a-three-generation-pedigree-presenting-with-intellectual-disability-with-childhood-onset-seizures
#1
Stacy Hewson, Klajdi Puka, Saadet Mercimek-Mahmutoglu
KCNQ2 has been reported as a frequent cause of autosomal dominant benign familial neonatal seizures. De novo likely pathogenic variants in KCNQ2 have been described in neonatal or early infantile onset epileptic encephalopathy patients. Here, we report a three-generation family with six affected patients with a novel likely pathogenic variant (c.628C>T; p.Arg210Cys) in KCNQ2. Four family members, three adults and a child, presented with a childhood seizure onset with variability in the severity of seizures and response to treatment, intellectual disability (ID) as well as behavioral problems...
June 11, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28575529/abnormal-%C3%AE-aminobutyric-acid-neurotransmission-in-a-kcnq2-model-of-early-onset-epilepsy
#2
Taku Uchida, Christoph Lossin, Yukiko Ihara, Masanobu Deshimaru, Yuchio Yanagawa, Susumu Koyama, Shinichi Hirose
OBJECTIVE: Mutations of the KCNQ2 gene, which encodes the Kv 7.2 subunit of voltage-gated M-type potassium channels, have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter gamma aminobutyric acid (GABA), which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient. METHODS: To examine whether KCNQ2-related neuronal hyperexcitability involves neonatally excitatory GABA, we examined 1-week-old knockin mice expressing the Kv 7...
June 2, 2017: Epilepsia
https://www.readbyqxmd.com/read/28544109/express-with-caution-epitope-tags-and-cdna-variants-effects-on-herg-channel-trafficking-half-life-and-function
#3
Marika L Osterbur Badhey, Alexander C Bertalovitz, Thomas V McDonald
INTRODUCTION: Genetic mutations in KCNQ2 which encodes hERG, the alpha subunit of the potassium channel responsible for the IKr current, cause Long QT Syndrome, an inherited cardiac arrhythmia disorder. Electrophysiology techniques are used to correlate genotype with molecular phenotype to determine which mutations identified in patients diagnosed Long QT Syndrome are disease causing, and which are benign. These investigations are usually done using heterologous expression in cell lines, and often, epitope fusion tags are used to enable isolation and identification of the protein of interest...
May 24, 2017: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/28525574/a-schizophrenia-related-deletion-leads-to-kcnq2-dependent-abnormal-dopaminergic-modulation-of-prefrontal-cortical-interneuron-activity
#4
Se Joon Choi, Jun Mukai, Mirna Kvajo, Bin Xu, Anastasia Diamantopoulou, Pothitos M Pitychoutis, Bin Gou, Joseph A Gogos, Hui Zhang
Altered prefrontal cortex function is implicated in schizophrenia (SCZ) pathophysiology and could arise from imbalance between excitation and inhibition (E/I) in local circuits. It remains unclear whether and how such imbalances relate to genetic etiologies. We used a mouse model of the SCZ-predisposing 22q11.2 deletion (Df(16)A+/- mice) to evaluate how this genetic lesion affects the excitability of layer V prefrontal pyramidal neurons and its modulation by dopamine (DA). Df(16)A+/- mice have normal balance between E/I at baseline but are unable to maintain it upon dopaminergic challenge...
May 19, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28503627/two-novel-kcnq2-mutations-in-2-families-with-benign-familial-neonatal-convulsions
#5
Ghalia Al Yazidi, Michael I Shevell, Myriam Srour
Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2, which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits...
January 2017: Child neurology open
https://www.readbyqxmd.com/read/28420012/vitamin-b6-responsive-epilepsy-due-to-a-novel-kcnq2-mutation
#6
Kerstin Alexandra Klotz, Johannes R Lemke, Rudolf Korinthenberg, Julia Jacobs
Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy...
April 18, 2017: Neuropediatrics
https://www.readbyqxmd.com/read/28399683/kcnq2-associated-neonatal-epilepsy-phenotype-might-correlate-with-genotype
#7
Inn-Chi Lee, Jiann-Jou Yang, Jao-Shwann Liang, Tung-Ming Chang, Shuan-Yow Li
We analyzed the KCNQ2 wild-type gene and 3 mutations to highlight the important association between the KCNQ2 phenotype and genotype. The clinical phenotypes of 3 mutations (p.E515D, p.V543 M, and p.R213Q) were compared. KCNQ2, wild-type, and mutant KCNQ2 alleles were transfected into HEK293 cells before whole-cell patch-clamp analysis. Neurodevelopmental outcomes were worst in patients with the p.R213Q mutation, better in patients with the p.E515D mutation, and best in patients with the novel p.V543 M mutation...
July 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/28387369/unexplained-early-infantile-epileptic-encephalopathy-in-han-chinese-children-next-generation-sequencing-and-phenotype-enriching
#8
Ahmed Arafat, Peng Jing, Yuping Ma, Miao Pu, Gai Nan, He Fang, Chen Chen, Yin Fei
Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures and progressive disturbance of cerebral function. This study was to investigate a cohort of Chinese children with unexplained EIEE, infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We used targeted next-generation sequencing to identify potential pathogenic variants of 308 genes in 68 Han Chinese patients with unexplained EIEE. A filter process was performed to prioritize rare variants of potential functional significance...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28387223/ethanol-withdrawal-drives-anxiety-related-behaviors-by-reducing-m-type-potassium-channel-activity-in-the-lateral-habenula
#9
Seungwoo Kang, Jing Li, Wanhong Zuo, Rao Fu, Danielle Gregor, Kresimir Krnjevic, Alex Bekker, Jiang-Hong Ye
Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K(+) channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs. We report here that in rats at 24 h withdrawal from systemic ethanol administration (either by intraperitoneal injection, 2 g/kg, twice/day, for 7 days; or intermittent drinking 20% ethanol in a two-bottle free choice protocol for 8 weeks), the basal firing rate and the excitability of LHb neurons in brain slices was higher, whereas the amplitude of medium afterhyperpolarization and M-type K(+) currents were smaller, when compared to ethanol naïve rats...
April 7, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28372301/endoplasmic-reticulum-retention-of-kcnq2-potassium-channel-mutants-following-temperature-elevation
#10
Fang Yu, Jian Xu, Zheman Xiao, Biwen Peng, Xiaohua He
BACKGROUND: KCNQ2 plays a key role in the regulation of neuronal excitability. The R214W and Y284C mutants of KCNQ2 channels, which are associated with BFNC, can decrease channel function to cause neuronal hyperexcitability and promote seizures. Previous studies revealed that elevated temperature caused up-regulation of KCNQ2 expression. OBJECTIVE: The present study sought to investigate the impact of temperature elevation on neuronal KCNQ2 ion channel mutants. METHODS: Protein expression of wt KCNQ2 and the R214W, Y284C and truncated selective filter mutants at different temperatures was detected by live-cell confocal fluorescence microscopy and by Western blotting...
2017: Bio-medical Materials and Engineering
https://www.readbyqxmd.com/read/28283543/kcnq-smit-complex-formation-facilitates-ion-channel-solute-transporter-cross-talk
#11
Daniel L Neverisky, Geoffrey W Abbott
Voltage-gated potassium channels formed by KCNQ2 and KCNQ3 are essential for normal neuronal excitability. KCNQ2/3 channel activity is augmented in vivo by phosphatidylinositol 4,5-bisphosphate (PIP2), which is generated from myo-inositol, an osmolyte transported into cells by sodium-dependent myo-inositol transporters (SMITs). Here, we discovered that KCNQ2/3 channels isoform-specifically colocalize with SMIT1 and SMIT2 at sciatic nerve nodes of Ranvier and in axon initial segments, and form channel-transporter complexes in vitro and in vivo KCNQ2/3 coexpression protected SMIT1 activity from the otherwise inhibitory effects of cellular depolarization imposed by elevating extracellular [K(+)], and KCNQ2 was required for potentiation of SMIT activity by myo-inositol preincubation...
March 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28139826/neonatal-nonepileptic-myoclonus-is-a-prominent-clinical-feature-of-kcnq2-gain-of-function-variants-r201c-and-r201h
#12
Sarah B Mulkey, Bruria Ben-Zeev, Joost Nicolai, John L Carroll, Sabine Grønborg, Yong-Hui Jiang, Nishtha Joshi, Megan Kelly, David A Koolen, Mohamad A Mikati, Kristen Park, Phillip L Pearl, Ingrid E Scheffer, Rebecca C Spillmann, Maurizio Taglialatela, Silvia Vieker, Sarah Weckhuysen, Edward C Cooper, Maria Roberta Cilio
OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course...
March 2017: Epilepsia
https://www.readbyqxmd.com/read/28133863/genetics-and-genotype-phenotype-correlations-in-early-onset-epileptic-encephalopathy-with-burst-suppression
#13
Heather E Olson, McKenna Kelly, Christopher M LaCoursiere, Rebecca Pinsky, Dimira Tambunan, Catherine Shain, Sriram Ramgopal, Masanori Takeoka, Mark H Libenson, Kristina Julich, Tobias Loddenkemper, Eric D Marsh, Devorah Segal, Susan Koh, Michael S Salman, Alex R Paciorkowski, Edward Yang, Ann M Bergin, Beth Rosen Sheidley, Annapurna Poduri
OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging...
March 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28125509/kcnq2-3-channel-agonist-flupirtine-reduces-cocaine-place-preference-in-rats
#14
James Mooney, Scott M Rawls
The efficacy of KCNQ2/3 channel agonists against drug reward has not been defined despite their ability to reduce locomotor-stimulant and dopamine-activating effects of psychostimulants. We tested the hypothesis that flupirtine (FLU) (2.5, 10, 20 mg/kg), a KCNQ2/3 agonist, reduces cocaine (15 mg/kg) conditioned place preference. FLU (20 mg/kg), injected concurrently with cocaine during conditioning, reduced the development of cocaine conditioned place preference. FLU (20 mg/kg) also reduced cocaine locomotor activation without affecting baseline activity...
January 25, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/28100740/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#15
Zachary Niday, Virginia E Hawkins, Heun Soh, Daniel K Mulkey, Anastasios V Tzingounis
KCNQ2 potassium channels are critical for normal brain function, as both loss-of-function and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28038823/a-kcnq2-e515d-mutation-associated-with-benign-familial-neonatal-seizures-and-continuous-spike-and-waves-during-slow-wave-sleep-syndrome-in-taiwan
#16
Inn-Chi Lee, Jiann-Jou Yang, Shuan-Yow Li
BACKGROUND/PURPOSE: Pediatric epilepsy caused by a KCNQ2 gene mutation usually manifests as benign familial neonatal seizures (BFNS) during the 1(st) week of life. However, the exact mechanism, phenotype, and genotype of the KCNQ2 mutation are unclear. METHODS: We studied the KCNQ2 genotype from 75 nonconsanguineous patients with childhood epilepsy without an identified cause (age range: from 2 days to 18 years) and from 55 healthy adult controls without epilepsy...
December 27, 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/27994149/fgf14-is-a-regulator-of-kcnq2-3-channels
#17
Juan Lorenzo Pablo, Geoffrey S Pitt
KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27965589/m-currents-kv7-2-7-3-kcnq2-kcnq3-are-responsible-for-dysfunctional-autonomic-control-in-hypertensive-rats
#18
Torill Berg
Autonomic dysfunctions play important roles in hypertension, heart failure and arrhythmia, often with a detrimental and fatal effect. The present study analyzed if these dysfunctions involved M-channels (members of the Kv7/KNCQ family) in spontaneously hypertensive rats (SHR). Cardiac output and heart rate (HR) were recorded by a flow probe on the ascending aorta in anesthetized SHR and normotensive rats (WKY), and blood pressure (BP) by a femoral artery catheter. Total peripheral vascular resistance (TPR) was calculated...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27920148/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#19
Zachary Niday, Virginia E Hawkins, Heun Soh, Daniel K Mulkey, Anastasios V Tzingounis
KCNQ2 potassium channels are critical for normal brain function, as both loss- and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels...
December 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27888506/rapid-and-safe-response-to-low-dose-carbamazepine-in-neonatal-epilepsy
#20
Tristan T Sands, Martina Balestri, Giulia Bellini, Sarah B Mulkey, Olivier Danhaive, Eliza Hayes Bakken, Maurizio Taglialatela, Michael S Oldham, Federico Vigevano, Gregory L Holmes, Maria Roberta Cilio
OBJECTIVE: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE). METHODS: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes. RESULTS: Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures...
December 2016: Epilepsia
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