| 1 | Nat. Med. 2009 May 15: 509-18 |
|---|---|
| PMID | 19412172 |
| Title | A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. |
| Abstract | Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Behav Brain Funct 2010 -1 6: 27 |
| PMID | 20507645 |
| Title | Two four-marker haplotypes on 7q36.1 region indicate that the potassium channel gene HERG1 (KCNH2, Kv11.1) is related to schizophrenia: a case control study. |
| Abstract | The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by HERG1 (KCNH2, Kv11.1) gene and is most highly expressed in heart and brain. Genetic variations in HERG1 predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia. We genotyped four single nucleotide polymorphisms (SNPs) in 7q36.1 region (two SNPs, rs1805123 and rs3800779, located on HERG1, and two SNPs, rs885684 and rs956642, at the 3'-downstream intergenic region) and then performed single SNP and haplotype association analyses in 84 patients with schizophrenia and 74 healthy controls after the exclusion of individuals having prolonged or shortened QT interval on electrocardiogram. Our analyses revealed that both genotype and allele frequencies of rs3800779 (c.307+585G>T) were significantly different between populations (P = 0.023 and P = 0.018, respectively). We also identified that two previously undescribed four-marker haplotypes which are nearly allelic opposite of each other and located in chr7:150225599-150302147bp position encompassing HERG1 were either overrepresented (A-A-A-T, the at-risk haplotype, P = 0.0007) or underrepresented (C-A-C-G, the protective haplotype, P = 0.005) in patients compared to controls. Our results indicate that the potassium channel gene HERG1 is related to schizophrenia. Our findings may also implicate the whole family of HERG channels (HERG1, HERG2 and HERG3) in the pathogenesis of psychosis and its treatment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neuropsychopharmacol Hung 2011 Dec 13: 205-10 |
| PMID | 22184188 |
| Title | Genetic predisposition to schizophrenia: what did we learn and what does the future hold? |
| Abstract | schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Am J Psychiatry 2012 Dec 169: 1318; author reply 1318-9 |
| PMID | 23212063 |
| Title | Genetic variation in KCNH2 and a unique hERG isoform in patients with schizophrenia: efficacy-safety link. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Am J Psychiatry 2012 Jul 169: 725-34 |
| PMID | 22706279 |
| Title | Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia. |
| Abstract | Antidopaminergic drugs bind to hERG1 potassium channels encoded by the gene KCNH2, which accounts for the side effect of QT interval prolongation. KCNH2 has also been associated with schizophrenia risk, and risk alleles predict increased expression of a brain-selective isoform, KCNH2 3.1, that has unique physiological properties. The authors assessed whether genetic variation associated with KCNH2 3.1 expression influences the therapeutic effects of antipsychotic drugs. The authors performed a pharmacogenetic analysis of antipsychotic treatment response in patients with schizophrenia using data from two independent studies: a National Institute of Mental Health (NIMH) double-blind, placebo-controlled inpatient crossover trial (N=54) and the multicenter outpatient Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (N=364). The KCNH2 genotype that was previously associated with increased expression of KCNH2 3.1 in the brain was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with the Positive and Negative Syndrome Scale. The authors also analyzed time to discontinuation in the olanzapine arm of the CATIE study. In the NIMH study, individuals who were homozygous for the KCNH2 3.1 increased expression-associated T allele of rs1036145 showed significant improvement in positive symptoms, general psychopathology, and thought disturbance, while patients with other genotypes showed little change. In the CATIE study, analogous significant genotypic effects were observed. Moreover, individuals who were homozygous for the T allele at rs1036145 were one-fifth as likely to discontinue olanzapine. These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brainspecific 3.1 isoform of KCNH2. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | World J. Biol. Psychiatry 2013 Mar 14: 114-20 |
| PMID | 21936766 |
| Title | The KCNH2 gene is associated with neurocognition and the risk of schizophrenia. |
| Abstract | A genetic variant (rs3800779; M30) in the KCNH2 gene has been associated with schizophrenia, a lower intelligence quotient (IQ) and processing speed scores, altered brain functions and increased KCNH2-3.1. mRNA levels in the hippocampus. The aims of this study were to investigate whether the KCNH2 polymorphism is associated with schizophrenia-related neurocognitive deficits and to confirm the association between the variant and schizophrenia. The effects of the risk genotype on IQ and seven neurocognitive batteries were examined by the analysis of covariance in 191 healthy subjects. We performed a meta-analysis of the association between M30 and schizophrenia using five independent ethnic groups (1,720 cases; 2,418 controls). Consistent with the previous study, we provided evidence that subjects with the risk T carriers had significantly lower IQ scores than those with the G/G genotype (P = 0.048). Of the seven neurocognitive batteries, subjects with the risk genotype demonstrated lower performances on attention/vigilance (P = 0.0079) and working memory (P = 0.0066) relative to subjects with the G/G genotype. Meta-analysis demonstrated evidence for an association between M30 and schizophrenia without showing heterogeneity across studies (odds ratio = 1.18; P = 0.0017). These data suggest that the KCNH2 polymorphism could be associated with schizophrenia-related neuropsychological deficits and the risk of developing schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | PLoS ONE 2014 -1 9: e98555 |
| PMID | 24887423 |
| Title | QT is longer in drug-free patients with schizophrenia compared with age-matched healthy subjects. |
| Abstract | The potassium voltage-gated channel KCNH2 is a well-known gene in which mutations induce familial QT interval prolongation. KCNH2 is suggested to be a risk gene for schizophrenia. Additionally, the disturbance of autonomic control, which affects the QT interval, is known in schizophrenia. Therefore, we speculate that schizophrenic patients have characteristic features in terms of the QT interval in addition to the effect of antipsychotic medication. The QT interval of patients with schizophrenia not receiving antipsychotics (n?=?85) was compared with that of patients with schizophrenia receiving relatively large doses of antipsychotics (n?=?85) and healthy volunteers (n?=?85). The QT interval was corrected using four methods (Bazett, Fridericia, Framingham or Hodges method). In ANCOVA with age and heart rate as covariates, patients not receiving antipsychotic treatment had longer QT intervals than did the healthy volunteers, but antipsychotics prolonged the QT interval regardless of the correction method used (P<0.01). schizophrenic patients with and without medication had a significantly higher mean heart rate than did the healthy volunteers, with no obvious sex-related differences in the QT interval. The QT interval prolongation may be manifestation of a certain biological feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | PLoS ONE 2014 -1 9: e98555 |
| PMID | 24887423 |
| Title | QT is longer in drug-free patients with schizophrenia compared with age-matched healthy subjects. |
| Abstract | The potassium voltage-gated channel KCNH2 is a well-known gene in which mutations induce familial QT interval prolongation. KCNH2 is suggested to be a risk gene for schizophrenia. Additionally, the disturbance of autonomic control, which affects the QT interval, is known in schizophrenia. Therefore, we speculate that schizophrenic patients have characteristic features in terms of the QT interval in addition to the effect of antipsychotic medication. The QT interval of patients with schizophrenia not receiving antipsychotics (n?=?85) was compared with that of patients with schizophrenia receiving relatively large doses of antipsychotics (n?=?85) and healthy volunteers (n?=?85). The QT interval was corrected using four methods (Bazett, Fridericia, Framingham or Hodges method). In ANCOVA with age and heart rate as covariates, patients not receiving antipsychotic treatment had longer QT intervals than did the healthy volunteers, but antipsychotics prolonged the QT interval regardless of the correction method used (P<0.01). schizophrenic patients with and without medication had a significantly higher mean heart rate than did the healthy volunteers, with no obvious sex-related differences in the QT interval. The QT interval prolongation may be manifestation of a certain biological feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Mol. Psychiatry 2016 Feb -1: -1 |
| PMID | 26857598 |
| Title | KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia. |
| Abstract | Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.Molecular Psychiatry advance online publication, 9 February 2016; doi:10.1038/mp.2015.219. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Am J Psychiatry 2016 Jan 173: 53-9 |
| PMID | 26481172 |
| Title | Differential Response to Risperidone in Schizophrenia Patients by KCNH2 Genotype and Drug Metabolizer Status. |
| Abstract | Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms. Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic |