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A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.

Grube S, Gerchen MF, Adamcio B, Pardo LA, Martin S, Malzahn D, Papiol S, Begemann M, Ribbe K, Friedrichs H, Radyushkin KA, Müller M, Benseler F, Riggert J, Falkai P, Bickeböller H, Nave KA, Brose N, Stühmer W, Ehrenreich H - EMBO Mol Med (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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SK3 CAG repeat lengths sum is associated with higher cognitive function in schizophrenia but does not constitute a genetic risk factor for the diseaseA.KCNN3 is located at 1q21.3 and spans 162.8 kbp. The nine exons (boxes) encode two different splicing variants (1, 2); the coding region is shaded in grey. The black line in exon1 indicates the position of the polymorphic CAG repeat.B. The region around the CAG repeat is highly conserved among species.C,D. Neither the distribution of the individual sum of repeat lengths of both alleles (C) nor that of the individual difference between repeat lengths of both alleles (D) is different between schizophrenic patients (n = 1060) and healthy controls (n = 1135). Hence, these readouts of the SK3 CAG repeat polymorphism do not support a genetic risk for developing schizophrenia.E,F. In contrast, the PGAS approach allows identification of a role for the SK3 CAG repeat polymorphism in higher cognitive function.E. Intercorrelation network of cognitive target variables (dark ovals) and cognitive control variables (light ovals) in the GRAS population of schizophrenic patients. Line thickness indicates the degree of correlation between two respective tests after standardization by Blom transformation and adjustment for covariates sex, age, antipsychotic medication and negative symptoms.F. Scatter plot of the covariate-adjusted composite score calculated as mean of all standardized (Blom transformed) cognitive target variables. Adjusted was for covariates sex, age, antipsychotic medication and negative symptoms. Linear regression analysis reveals a significant effect (p < 0.0001) of allelic repeat lengths sum on the composite score.
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fig01: SK3 CAG repeat lengths sum is associated with higher cognitive function in schizophrenia but does not constitute a genetic risk factor for the diseaseA.KCNN3 is located at 1q21.3 and spans 162.8 kbp. The nine exons (boxes) encode two different splicing variants (1, 2); the coding region is shaded in grey. The black line in exon1 indicates the position of the polymorphic CAG repeat.B. The region around the CAG repeat is highly conserved among species.C,D. Neither the distribution of the individual sum of repeat lengths of both alleles (C) nor that of the individual difference between repeat lengths of both alleles (D) is different between schizophrenic patients (n = 1060) and healthy controls (n = 1135). Hence, these readouts of the SK3 CAG repeat polymorphism do not support a genetic risk for developing schizophrenia.E,F. In contrast, the PGAS approach allows identification of a role for the SK3 CAG repeat polymorphism in higher cognitive function.E. Intercorrelation network of cognitive target variables (dark ovals) and cognitive control variables (light ovals) in the GRAS population of schizophrenic patients. Line thickness indicates the degree of correlation between two respective tests after standardization by Blom transformation and adjustment for covariates sex, age, antipsychotic medication and negative symptoms.F. Scatter plot of the covariate-adjusted composite score calculated as mean of all standardized (Blom transformed) cognitive target variables. Adjusted was for covariates sex, age, antipsychotic medication and negative symptoms. Linear regression analysis reveals a significant effect (p < 0.0001) of allelic repeat lengths sum on the composite score.

Mentions: The CAG repeat polymorphism in the KCNN3 exon 1 coding region has been described in several primate species (Fig 1A and B). We first conducted a case-control study to explore a potential role of the KCNN3 CAG repeat lengths sum of both alleles as a genetic risk factor for schizophrenia. No significant difference in the distribution of repeat lengths sum between cases (n = 1060) and healthy controls (n = 1135) was found (Fig 1C; χ2 = 5.69, p = 0.82, evaluated with Monte Carlo sampling on 1000 runs; for details see Supporting information). Also, no gender influence was observed. An association analysis of single allele repeat lengths instead of allelic repeat lengths sum between cases and controls did not yield significant distribution differences either (data not shown). Furthermore, the intra individual difference of repeat lengths as a measure of marker heterogeneity did not vary significantly between cases and controls (Fig 1D; χ2 = 4.12, p = 0.65, 1000 Monte Carlo simulations). Thus, as assumed, there is no evidence for a role of the SK3 CAG repeat length in the risk to develop schizophrenia.


A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.

Grube S, Gerchen MF, Adamcio B, Pardo LA, Martin S, Malzahn D, Papiol S, Begemann M, Ribbe K, Friedrichs H, Radyushkin KA, Müller M, Benseler F, Riggert J, Falkai P, Bickeböller H, Nave KA, Brose N, Stühmer W, Ehrenreich H - EMBO Mol Med (2011)

SK3 CAG repeat lengths sum is associated with higher cognitive function in schizophrenia but does not constitute a genetic risk factor for the diseaseA.KCNN3 is located at 1q21.3 and spans 162.8 kbp. The nine exons (boxes) encode two different splicing variants (1, 2); the coding region is shaded in grey. The black line in exon1 indicates the position of the polymorphic CAG repeat.B. The region around the CAG repeat is highly conserved among species.C,D. Neither the distribution of the individual sum of repeat lengths of both alleles (C) nor that of the individual difference between repeat lengths of both alleles (D) is different between schizophrenic patients (n = 1060) and healthy controls (n = 1135). Hence, these readouts of the SK3 CAG repeat polymorphism do not support a genetic risk for developing schizophrenia.E,F. In contrast, the PGAS approach allows identification of a role for the SK3 CAG repeat polymorphism in higher cognitive function.E. Intercorrelation network of cognitive target variables (dark ovals) and cognitive control variables (light ovals) in the GRAS population of schizophrenic patients. Line thickness indicates the degree of correlation between two respective tests after standardization by Blom transformation and adjustment for covariates sex, age, antipsychotic medication and negative symptoms.F. Scatter plot of the covariate-adjusted composite score calculated as mean of all standardized (Blom transformed) cognitive target variables. Adjusted was for covariates sex, age, antipsychotic medication and negative symptoms. Linear regression analysis reveals a significant effect (p < 0.0001) of allelic repeat lengths sum on the composite score.
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fig01: SK3 CAG repeat lengths sum is associated with higher cognitive function in schizophrenia but does not constitute a genetic risk factor for the diseaseA.KCNN3 is located at 1q21.3 and spans 162.8 kbp. The nine exons (boxes) encode two different splicing variants (1, 2); the coding region is shaded in grey. The black line in exon1 indicates the position of the polymorphic CAG repeat.B. The region around the CAG repeat is highly conserved among species.C,D. Neither the distribution of the individual sum of repeat lengths of both alleles (C) nor that of the individual difference between repeat lengths of both alleles (D) is different between schizophrenic patients (n = 1060) and healthy controls (n = 1135). Hence, these readouts of the SK3 CAG repeat polymorphism do not support a genetic risk for developing schizophrenia.E,F. In contrast, the PGAS approach allows identification of a role for the SK3 CAG repeat polymorphism in higher cognitive function.E. Intercorrelation network of cognitive target variables (dark ovals) and cognitive control variables (light ovals) in the GRAS population of schizophrenic patients. Line thickness indicates the degree of correlation between two respective tests after standardization by Blom transformation and adjustment for covariates sex, age, antipsychotic medication and negative symptoms.F. Scatter plot of the covariate-adjusted composite score calculated as mean of all standardized (Blom transformed) cognitive target variables. Adjusted was for covariates sex, age, antipsychotic medication and negative symptoms. Linear regression analysis reveals a significant effect (p < 0.0001) of allelic repeat lengths sum on the composite score.
Mentions: The CAG repeat polymorphism in the KCNN3 exon 1 coding region has been described in several primate species (Fig 1A and B). We first conducted a case-control study to explore a potential role of the KCNN3 CAG repeat lengths sum of both alleles as a genetic risk factor for schizophrenia. No significant difference in the distribution of repeat lengths sum between cases (n = 1060) and healthy controls (n = 1135) was found (Fig 1C; χ2 = 5.69, p = 0.82, evaluated with Monte Carlo sampling on 1000 runs; for details see Supporting information). Also, no gender influence was observed. An association analysis of single allele repeat lengths instead of allelic repeat lengths sum between cases and controls did not yield significant distribution differences either (data not shown). Furthermore, the intra individual difference of repeat lengths as a measure of marker heterogeneity did not vary significantly between cases and controls (Fig 1D; χ2 = 4.12, p = 0.65, 1000 Monte Carlo simulations). Thus, as assumed, there is no evidence for a role of the SK3 CAG repeat length in the risk to develop schizophrenia.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Show MeSH
Related in: MedlinePlus