A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in 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.
Affiliation: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.Show MeSH
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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.
Affiliation: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.