BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

• MeSH
• dítě MeSH
• draslíkové kanály ether-a-go-go * genetika   MeSH
• epilepsie generalizovaná * genetika   MeSH
• epilepsie * genetika   MeSH
• fenotyp MeSH
• lidé MeSH
• mutace MeSH
• novorozenec MeSH
• záchvaty genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Out-of-hospital cardiac arrest in pediatric population is rare and predominantly has respiratory aetiology. Authors present the relatively unique case of out-of hospital cardiac arrest in 5-years old pediatric patient due to ventricular fibrillation (VF) as the initial rhythm during the advanced life support. The patient was resuscitated by his parents and the initial rhythm was VF. After defibrillation the patient was admitted to the pediatric intensive care were another two episodes of VF was detected and treated. After standard postresuscitation care, patient was weaned from sedation and extubated with good neurologic outcome. Genetic screening of the 7 genes associated with cardiac channelopathies (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2, CASQ2) found mutation in gene KCHN2 and gene SCN5A, that were according to actual data considered benign. This case highlights the need for automated external defibrillator implementation in basic life support also in pediatric population and possible role of genetic predisposition in emergence of fibrillation.

• MeSH
• draslíkový kanál ERG1 MeSH
• fibrilace komor genetika   terapie   MeSH
• genetická predispozice k nemoci MeSH
• kardiopulmonální resuscitace MeSH
• lidé MeSH
• mutace MeSH
• napěťově řízený sodíkový kanál, typ 5 MeSH
• předškolní dítě MeSH
• zástava srdce mimo nemocnici genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Lidský ether-à-go-go příbuzný gen (hERG; oficiálně označovaný jako KCNH2), kóduje strukturu proteinu tvořícího α podjednotku napěťově řízeného iontového kanálu, který vede rychlou složku opožděného K+ proudu z buňky (IKr). Tento proud hraje významnou úlohu zejména v repolarizaci srdečních buněk. Mutace v genu hERG vedou k projevům dědičných syndromů, které jsou charakteristické prodloužením nebo zkrácením intervalu QT na elektro­kardiogramu a vznikem život ohrožujících arytmií. Tato práce představuje kanály hERG i jako součást regulačních mechanizmů kontraktilní činnosti hladkého svalstva, aktivity neuronů, uvolňování některých hormonů i proliferace a apoptózy nádorových buněk. Zmíněná jsou rovněž onemocnění plynoucí z poruchy funkce těchto kanálů a také možnosti využití genu/kanálu hERG jakožto diagnostického markeru a možného terapeutického cíle u různých onemocnění, zejména u nádorových.

The human ether-à-go-go related gene (hERG; officially designated as KCNH2) encodes the structure of protein forming α-subunit of voltage-gated ion channel which conducts the rapid component of delayed rectifier K+ current (IKr). This current plays an important role namely in the cardiac repolarization. Mutations in hERG result in inherited arrhythmogenic syndromes characterized by a lenghtening or shortening of QT interval on the electrocardiogram and by an increased occurrence of life-threatening arrhythmias. This review also introduces hERG channels as a part of regulatory mechanisms of the smooth muscle contractility, neuronal activity, release of several hormones, and of proliferation and apoptosis of cancer cells. There are also mentioned some of the diseases arising from hERG channel dysfunction, and some possibilities of use of hERG gene/channel as a diagnostic marker and potential therapeutic target in various diseases, namely in cancer.

• MeSH
• apoptóza MeSH
• draslíkový kanál ERG1 * fyziologie   terapeutické užití   MeSH
• endokrinní buňky sekrece   MeSH
• epilepsie MeSH
• hladké svalstvo patologie   MeSH
• lidé MeSH
• membránové potenciály MeSH
• mutace genetika   MeSH
• nádory farmakoterapie   MeSH
• nervová tkáň patologie   MeSH
• proliferace buněk MeSH
• schizofrenie MeSH
• svalová kontrakce MeSH
• syndrom dlouhého QT diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH

Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD.

• MeSH
• arginin chemie   MeSH
• databáze proteinů MeSH
• draslíkový kanál ERG1 chemie   MeSH
• gating iontového kanálu MeSH
• guanidin chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• lysin chemie   MeSH
• protein - isoformy chemie   MeSH
• sekvence aminokyselin MeSH
• simulace molekulární dynamiky * MeSH
• statická elektřina MeSH
• strukturní homologie proteinů MeSH
• voda chemie   MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Inhibition of the cardiac human ether-a-go-go-related gene channel is a problematic off-target pharmacological activity and, hence, a major safety liability in clinical practice. Several non-cardiac drugs have been restricted in their use, or even removed from the market due to this potentially fatal adverse effect. Comparatively little is known about the human ether-a-go-go-related gene inhibitory potential of plant-derived compounds. In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by ≥ 50% at 100 µM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.

• MeSH
• akční potenciály účinky léků   MeSH
• alkaloidy farmakologie   MeSH
• berberinové alkaloidy farmakologie   MeSH
• biologické přípravky farmakologie   MeSH
• blokátory draslíkových kanálů farmakologie   MeSH
• draslíkové kanály ether-a-go-go antagonisté a inhibitory   MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• metoda terčíkového zámku MeSH
• oocyty MeSH
• Xenopus laevis MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Classic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. METHODS AND RESULTS: One hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. CONCLUSIONS: Incidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.

• MeSH
• dospělí MeSH
• draslíkové kanály ether-a-go-go genetika   MeSH
• elektrokardiografie statistika a číselné údaje   MeSH
• genetická predispozice k nemoci epidemiologie   genetika   MeSH
• hodnocení rizik MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• prevalence MeSH
• reprodukovatelnost výsledků MeSH
• RNA dlouhá nekódující genetika   MeSH
• senzitivita a specificita MeSH
• syndrom dlouhého QT diagnóza   epidemiologie   genetika   MeSH
• zátěžový test statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH