| 1 | Am. J. Med. Genet. 2000 Dec 96: 744-8 |
|---|---|
| PMID | 11121173 |
| Title | Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia. |
| Abstract | Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of approximately 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes > or = 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:744-748, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Am. J. Med. Genet. 2000 -1 97: 77-97 |
| PMID | 10813808 |
| Title | The unstable trinucleotide repeat story of major psychosis. |
| Abstract | New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes in major psychosis have also shown some intriguing results. These findings, reviewed here, suggest that, although a major role for unstable trinucleotides in psychosis is unlikely, involvement at a more modest level in a minority of cases cannot be excluded, and warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Hum. Genet. 2001 -1 46: 463-70 |
| PMID | 11501944 |
| Title | Genomic organization and promoter analysis of human KCNN3 gene. |
| Abstract | KCNN3 is a member of the gene family, KCNN1-4, encoding the small and intermediate conductance calcium-activated potassium channels. Long CAG-repeat alleles of this gene have been found to be over-represented in patients with schizophrenia in a number of population-based association studies, and this gene maps to human chromosome 1q21, a region recently implicated in schizophrenia by linkage. To set the stage for a further functional evaluation of KCNN3, we defined the nature of the genomic locus in the size, structure, and sequence of its introns and exons and the function of potential upstream regulatory regions. We isolated P1-derived artificial chromosome (PAC) clones from a genomic library and identified an overlapping available bacterial artificial chromosome (BAC) clone. Cosmids subcloned from the PAC and BAC clones were then sequenced and merged with the sequence in the public database. The KCNN3 gene spans over 163.1 kb and is composed of eight exons and seven introns. All of the exon-intron junctions conform closely to consensus splice sites. The proximal 2.5 kb of the 5'-flanking sequence was obtained and analyzed for potential transcription factor binding sites. In the proximal 2.5 kb upstream region, potential sites for the Ikaros factor (IK2), homeodomain factor Nkx-2.5/Csx (NKX25), nuclear factor of activated T-cells (NFAT), upstream stimulating factor (USF), c-AMP responsive element binding protein (CREB), POU factor Brn2 (BRN-2), myeloid zinc finger protein (MZF1), vitellogenin binding protein (VBP), HNF3 forkhead homologue 2 (HFH2), and transcription initiation were identified, as well as several potential AP-1 and AP-4 sites. Finally, a 2261-bp fragment of this upstream region was cloned into a promoterless pGL3-luciferase vector, where it produced orientation-dependent expression of the reporter gene in transiently transfected PC12 cells, cells which natively express functional KCNN3 channels, suggesting that this cloned fragment includes competent promoter elements of this gene. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Psychiatry Res 2001 Apr 101: 203-7 |
| PMID | 11311923 |
| Title | Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. |
| Abstract | To investigate a possible involvement of expanded triplet repeats of genome in the genomes of patients with endogenous psychoses, we examined a CAG repeat polymorphism in the coding region of the KCNN3 gene in schizophrenia, schizoaffective disorder, bipolar disorder and controls of the Japanese population. There were no significant differences in the CAG repeat number of longer or shorter alleles among the four diagnostic groups or among the schizophrenia hebephrenic and paranoid subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J. Biol. Chem. 2001 Jul 276: 27753-6 |
| PMID | 11395478 |
| Title | Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia. |
| Abstract | The small conductance calcium-activated K+ channel gene SKCa3/KCNN3 maps to 1q21, a region strongly linked to schizophrenia. Recently, a 4-base pair deletion in SKCa3 was reported in a patient with schizophrenia, which truncates the protein at the end of the N-terminal cytoplasmic region (SKCa3Delta). We generated a green fluorescent protein-SKCa3 N-terminal construct (SKCa3-1/285) that is identical to SKCa3Delta except for the last two residues. Using confocal microscopy we demonstrate that SKCa3-1/285 localizes rapidly and exclusively to the nucleus of mammalian cells like several other pathogenic polyglutamine-containing proteins. This nuclear targeting is mediated in part by two polybasic sequences present at the C-terminal end of SKCa3-1/285. In contrast, full-length SKCa3, SKCa2, and IKCa1 polypeptides are all excluded from the nucleus and express as functional channels. When overexpressed in human Jurkat T cells, SKCa3-1/285 can suppress endogenous SKCa2 currents but not voltage-gated K+ currents. This dominant-negative suppression is most likely mediated through the co-assembly of SKCa3-1/285 with native subunits and the formation of non-functional tetramers. The nuclear localization of SKCa3-1/285 may alter neuronal architecture, and its ability to dominantly suppress endogenous small conductance K(Ca) currents may affect patterns of neuronal firing. Together, these two effects may play a part in the pathogenesis of schizophrenia and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | J. Neurosci. 2001 May 21: 3443-56 |
| PMID | 11331374 |
| Title | Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. |
| Abstract | The physiological activity of dopaminergic midbrain (DA) neurons is important for movement, cognition, and reward. Altered activity of DA neurons is a key finding in schizophrenia, but the cellular mechanisms have not been identified. Recently, KCNN3, a gene that encodes a member (SK3) of the small-conductance, calcium-activated potassium (SK) channels, has been proposed as a candidate gene for schizophrenia. However, the functional role of SK3 channels in DA neurons is unclear. We combined patch-clamp recordings with single-cell RT-PCR and confocal immunohistochemistry in mouse midbrain slices to study the function of molecularly defined SK channels in DA neurons. Biophysical and pharmacological analysis, single-cell mRNA, and protein expression profiling strongly suggest that SK3 channels mediate the calcium-dependent afterhyperpolarization in DA neurons. Perforated patch recordings of DA neurons in the substantia nigra (SN) demonstrated that SK3 channels dynamically control the frequency of spontaneous firing. In addition, SK3 channel activity was essential to maintain the high precision of the intrinsic pacemaker of DA SN neurons. In contrast, in the ventral tegmental area, DA neurons displayed significantly smaller SK currents and lower SK3 protein expression. In these DA neurons, SK3 channels were not involved in pacemaker control. Accordingly, they discharged in a more irregular manner compared with DA SN neurons. Thus, our study shows that differential SK3 channel expression is a critical molecular mechanism in DA neurons to control neuronal activity. This provides a cellular framework to understand the functional consequences of altered SK3 expression, a candidate disease mechanism for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Biol. Psychiatry 2002 May 51: 788-94 |
| PMID | 12007452 |
| Title | An association of CAG repeats at the KCNN3 locus with symptom dimensions of schizophrenia. |
| Abstract | In 1999 Cardno et al reported that long CAG repeats in the calcium-activated potassium channel gene hSKCa3/KCNN3 are associated with higher negative symptom dimension scores in schizophrenia patients. There has been no attempt to replicate the results. In this study, we investigated whether a symptom polymorphism of schizophrenia is associated with both the CAG repeat numbers and the difference in allele sizes. We tested the association of CAG repeats with symptom models of schizophrenia in 117 unrelated Jewish patients. A multivariate analysis (MANOVA) of two models of schizophrenia with the repeat distribution and the difference in allele sizes was performed. We found a significant positive association of the number of CAG repeats with negative syndrome, anergia, activation, and paranoid symptoms. In addition, nonparanoid schizophrenia patients who had differences in allele sizes were characterized by earlier onset of illness. The study supports the hypothesis that the combined effect of long CAG repeats and the differences in allele sizes contribute to symptom expression of schizophrenia, particularly on the anergia-activation-paranoid axis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Psychiatr. Genet. 2003 Sep 13: 143-50 |
| PMID | 12960745 |
| Title | Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis. |
| Abstract | Several studies reported contradictory findings regarding the association of major psychosis with CAG repeats in the KCNN3 gene. We investigated the contribution of the CAG repeat at the KCNN3 gene, localized to chromosome 1q21.3, to the genetic susceptibility for schizophrenia, schizoaffective and bipolar disorders. Analysis of the number of CAG repeats and the differences in allele length were performed for Israeli Ashkenazi Jews, non-Ashkenazi Jews, and Arabs diagnosed with major psychosis (n=181) versus matched ethnic controls (n=207). We found no significant difference in the number of CAG repeats between the entire sample of patients and controls. However, an analysis of the differences of allele length revealed a significantly greater number of patients with identical allele length (43.1%) when compared with normal controls (30.4%). Furthermore, an earlier age of non-paranoid schizophrenia onset was found associated with differences in allele sizes. There were no significant differences in the number of CAG repeats and the differences in allele length when subjects were grouped according to gender, ethnic origins of their parents, family history, and diagnostic groups. Our results support the hypothesis that a contribution of the KCNN3 gene to genetic susceptibility to major psychosis and their phenotypic polymorphism may be related to the difference of allele length rather than to the number of CAG repeats. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Aug 121B: 14-20 |
| PMID | 12898569 |
| Title | CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies. |
| Abstract | schizophrenia and bipolar disorder both show some evidence for genetic anticipation. In addition, significant expansion of anonymous CAG repeats throughout the genome has been detected in both of these disorders. The gene KCNN3, which codes for a small/intermediate conductance, calcium-regulated potassium channel, contains a highly polymorphic CAG-repeat array in exon 1. Initial evidence for association of both schizophrenia and bipolar disorder with increased CAG-repeat length of KCNN3 has not been consistently replicated. In the present study, we performed several meta-analyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders. Each group of studies was analyzed under two models, including a test for direct association with repeat length, and a test for association with dichotomized repeat-length groups. No evidence for a linear relationship between disease risk and repeat length was observed, as all pooled odds ratios approximated 1.0. Results of dichotomized allele-group analyses were more variable, especially for schizophrenia, where case-control studies found a significant association with longer repeats but family-based studies implicated shorter alleles. The results of these meta-analyses demonstrate that the risks for both schizophrenia and bipolar disorder are largely, if not entirely, independent of CAG-repeat length in exon 1 of KCNN3. This study cannot exclude the possibility that some aspect of this polymorphism, such as repeat-length disparity in heterozygotes, influences risk for these disorders. Further, it remains unknown if this polymorphism, or one in linkage disequilibrium with it, contributes to some distinct feature of the disorder, such as symptom severity or anticipation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Mol. Psychiatry 2003 May 8: 524-35, 460 |
| PMID | 12808432 |
| Title | Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. |
| Abstract | The small-conductance calcium-activated K(+) channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa. We have identified a novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3. SK3-1B, mRNA is widely distributed in human tissues and is present at 20-60% of SK3 in the brain. The SK3-1B protein lacks the N-terminus and first transmembrane segment, and begins eight residues upstream of the second transmembrane segment. When expressed alone, SK3-1B did not produce functional channels, but selectively suppressed endogenous SK3 currents in the pheochromocytoma cell line, PC12, in a dominant-negative fashion. This dominant inhibitory effect extended to other members of the SK subfamily, but not to voltage-gated K(+) channels, and appears to be due to intracellular trapping of endogenous SK channels. The effect of SK3-1B expression is very similar to that produced by expression of the rare SK3 truncation allele, SK3-Delta, found in a patient with schizophrenia. Regulation of SK3 and SK3-1B levels may provide a potent mechanism to titrate neuronal firing rates and neurotransmitter release in monoaminergic neurons, and alterations in the relative abundance of these proteins could contribute to abnormal neuronal excitability, and to the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jan 116B: 45-50 |
| PMID | 12497613 |
| Title | CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia. |
| Abstract | The purpose of this study was to determine whether genetic linkage or association could be observed between schizophrenia (SZ) and the CAG repeat polymorphisms within the genes KCNN3 (known previously as hSKCa3) and PPP2R2B (linked to Spino-Cerebellar Atrophy 12) in the Xhosa population in South Africa. Neither locus has been studied previously in African populations. The polymorphisms were genotyped in 589 individuals to form samples for Transmission Disequilibrium Test (TDT) analysis (176 unrelated probands, 145 with both parents and 30 with one parent genotyped), linkage analysis (49 families with 54 independent affected sib pairs [ASPs]), and case-control analyses (67 familial cases with a first-degree SZ relative, 101 sporadic cases with no affected first- or second-degree relative, and 90 control cases). No significant differences were found among familial cases, sporadic cases and controls in allele sizes (Kruskal-Wallis tests) or the numbers of alleles with sizes above and below the mean size for each polymorphism. Allele size was not correlated with age of onset (Spearman correlation). No significant evidence for association was observed using TDT analyses for all triads and separately for the familial triads. No significant evidence for linkage was observed for either locus with affected sib pair analysis using the possible triangle method or with Non-Parametric Linkage (NPL) analysis of the multiplex families. In conclusion, no significant evidence for linkage or association with SZ was observed for either polymorphism in this population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Nov 131B: 76-80 |
| PMID | 15389773 |
| Title | CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population. |
| Abstract | The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005 Aug 22: 441-3 |
| PMID | 16086287 |
| Title | [Transmission disequilibrium analysis of 1137-1140 Del GTGA frameshift mutation within the KCNN3 gene and schizophrenia based on family trios]. |
| Abstract | To investigate the relationship between 1137-1140 Del GTGA in exon 1 at KCNN3 gene and schizophrenia. The study included 289 subjects (affected 107; unaffected 182) from 95 schizophrenic trios. All subjects were collected from Han Chinese in south China and genotyped for 1137-1140 Del GTGA in KCNN3 using PCR and restriction endonuclease Dde I. All the affected patients met the CCMD-II-R criteria for schizophrenia. The haplotype-based haplotype relative risk(HHRR) and transmission/disequilibrium test(TDT) analyses were done in 95 schizophrenic trios. Comparative analysis on the distribution of alleles between the affected and unaffected parents(87 family trios) showed no significant difference(X(2)=0.253, P> 0.05). HHRR showed that KCNN3 gene alleles transmitted to the patients were not different from that of the non-transmitted parental alleles(X(2)=0.042, P> 0.05). TDT revealed that A(2) alleles were not preferentially transmitted to schizophrenic patients(X(2)=3.000, P=0.0833). In this study a lower frequency for 1137-1140 Del homozygote of KCNN3 gene was observed, and the HHRR and TDT analyses suggested that the 1137-1140 Del alleles of KCNN3 gene be unlikely to confer susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005 Aug 22: 441-3 |
| PMID | 16086287 |
| Title | [Transmission disequilibrium analysis of 1137-1140 Del GTGA frameshift mutation within the KCNN3 gene and schizophrenia based on family trios]. |
| Abstract | To investigate the relationship between 1137-1140 Del GTGA in exon 1 at KCNN3 gene and schizophrenia. The study included 289 subjects (affected 107; unaffected 182) from 95 schizophrenic trios. All subjects were collected from Han Chinese in south China and genotyped for 1137-1140 Del GTGA in KCNN3 using PCR and restriction endonuclease Dde I. All the affected patients met the CCMD-II-R criteria for schizophrenia. The haplotype-based haplotype relative risk(HHRR) and transmission/disequilibrium test(TDT) analyses were done in 95 schizophrenic trios. Comparative analysis on the distribution of alleles between the affected and unaffected parents(87 family trios) showed no significant difference(X(2)=0.253, P> 0.05). HHRR showed that KCNN3 gene alleles transmitted to the patients were not different from that of the non-transmitted parental alleles(X(2)=0.042, P> 0.05). TDT revealed that A(2) alleles were not preferentially transmitted to schizophrenic patients(X(2)=3.000, P=0.0833). In this study a lower frequency for 1137-1140 Del homozygote of KCNN3 gene was observed, and the HHRR and TDT analyses suggested that the 1137-1140 Del alleles of KCNN3 gene be unlikely to confer susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Int. J. Neurosci. 2006 Feb 116: 157-64 |
| PMID | 16393881 |
| Title | Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population. |
| Abstract | KCNN3 might be a candidate gene for schizophrenia. The KCNN3 cDNA sequence contains two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein. The second CAG repeat is highly polymorphic in the Caucasian population from both Europe and United States. The authors carried out a study to compare the allelic frequency distribution of the CAG repeat in KCNN3 gene in 55 Serbian schizophrenic patients and 46 controls. The data indicate a significant association between longer CAG repeats in second polymorphic KCNN3 region and schizophrenia in the Serbian population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Int. J. Neurosci. 2006 Feb 116: 157-64 |
| PMID | 16393881 |
| Title | Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population. |
| Abstract | KCNN3 might be a candidate gene for schizophrenia. The KCNN3 cDNA sequence contains two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein. The second CAG repeat is highly polymorphic in the Caucasian population from both Europe and United States. The authors carried out a study to compare the allelic frequency distribution of the CAG repeat in KCNN3 gene in 55 Serbian schizophrenic patients and 46 controls. The data indicate a significant association between longer CAG repeats in second polymorphic KCNN3 region and schizophrenia in the Serbian population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Neurosci. Lett. 2011 Jan 487: 61-5 |
| PMID | 20933057 |
| Title | No association between the KCNH1, KCNJ10 and KCNN3 genes and schizophrenia in the Han Chinese population. |
| Abstract | schizophrenia is a common severe mental illness affecting 0.3-2.0% of the world's population. The potassium channels are thought to have a role in modulating electrical excitability in neurons, regulating calcium signaling in oligodendrocytes and regulating action potential duration in presynaptic terminals and GABA release. Previous studies have reported that some potassium channel genes might be candidate genes for susceptibility to schizophrenia. In the present study, we chose three potassium channel genes, KCNH1, KCNJ10, KCNN3 to investigate the role of potassium channels in schizophrenia by genotyping 23 SNPs (9 in KCNH1, 5 in KCNJ10 and 9 in KCNN3) in a Han Chinese sample consisting of 893 schizophrenia patients and 611 healthy controls. No significant difference in allelic or genotypic frequency was revealed between schizophrenia patients and healthy individuals. Nor was a significant difference in haplotypic distribution detected. MDR analysis revealed no gene-gene interaction within the three potassium channel genes. Our study suggests that the 23 SNPs within the three potassium genes we examined do not play a major role in schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | EMBO Mol Med 2011 Jun 3: 309-19 |
| PMID | 21433290 |
| Title | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. |
| Abstract | KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype-based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells. In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans. To conclude, KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | EMBO Mol Med 2011 Jun 3: 309-19 |
| PMID | 21433290 |
| Title | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. |
| Abstract | KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype-based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells. In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans. To conclude, KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic |