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.
authors: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: Sabrina
authors: S
authors: Grube
authors: Martin F
authors: MF
authors: Gerchen
authors: Bartosz
authors: B
authors: Adamcio
authors: Luis A
authors: LA
authors: Pardo
authors: Sabine
authors: S
authors: Martin
authors: Dörthe
authors: D
authors: Malzahn
authors: Sergi
authors: S
authors: Papiol
authors: Martin
authors: M
authors: Begemann
authors: Katja
authors: K
authors: Ribbe
authors: Heidi
authors: H
authors: Friedrichs
authors: Konstantin A
authors: KA
authors: Radyushkin
authors: Michael
authors: M
authors: Müller
authors: Fritz
authors: F
authors: Benseler
authors: Joachim
authors: J
authors: Riggert
authors: Peter
authors: P
authors: Falkai
authors: Heike
authors: H
authors: Bickeböller
authors: Klaus-Armin
authors: KA
authors: Nave
authors: Nils
authors: N
authors: Brose
authors: Walter
authors: W
authors: Stühmer
authors: Hannelore
authors: H
authors: Ehrenreich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D003071:Cognition / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000235:genetics*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics* / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C406328:KCNN3 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels