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A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia
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 t...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377084/ https://www.ncbi.nlm.nih.gov/pubmed/21433290 http://dx.doi.org/10.1002/emmm.201100135 |
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author | Grube, Sabrina Gerchen, Martin F Adamcio, Bartosz Pardo, Luis A Martin, Sabine Malzahn, Dörthe Papiol, Sergi Begemann, Martin Ribbe, Katja Friedrichs, Heidi Radyushkin, Konstantin A Müller, Michael Benseler, Fritz Riggert, Joachim Falkai, Peter Bickeböller, Heike Nave, Klaus-Armin Brose, Nils Stühmer, Walter Ehrenreich, Hannelore |
author_facet | Grube, Sabrina Gerchen, Martin F Adamcio, Bartosz Pardo, Luis A Martin, Sabine Malzahn, Dörthe Papiol, Sergi Begemann, Martin Ribbe, Katja Friedrichs, Heidi Radyushkin, Konstantin A Müller, Michael Benseler, Fritz Riggert, Joachim Falkai, Peter Bickeböller, Heike Nave, Klaus-Armin Brose, Nils Stühmer, Walter Ehrenreich, Hannelore |
author_sort | Grube, Sabrina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3377084 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-33770842012-09-17 A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia Grube, Sabrina Gerchen, Martin F Adamcio, Bartosz Pardo, Luis A Martin, Sabine Malzahn, Dörthe Papiol, Sergi Begemann, Martin Ribbe, Katja Friedrichs, Heidi Radyushkin, Konstantin A Müller, Michael Benseler, Fritz Riggert, Joachim Falkai, Peter Bickeböller, Heike Nave, Klaus-Armin Brose, Nils Stühmer, Walter Ehrenreich, Hannelore EMBO Mol Med Research Article 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. WILEY-VCH Verlag 2011-06 /pmc/articles/PMC3377084/ /pubmed/21433290 http://dx.doi.org/10.1002/emmm.201100135 Text en Copyright © 2011 EMBO Molecular Medicine |
spellingShingle | Research Article Grube, Sabrina Gerchen, Martin F Adamcio, Bartosz Pardo, Luis A Martin, Sabine Malzahn, Dörthe Papiol, Sergi Begemann, Martin Ribbe, Katja Friedrichs, Heidi Radyushkin, Konstantin A Müller, Michael Benseler, Fritz Riggert, Joachim Falkai, Peter Bickeböller, Heike Nave, Klaus-Armin Brose, Nils Stühmer, Walter Ehrenreich, Hannelore A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title_full | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title_fullStr | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title_full_unstemmed | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title_short | A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia |
title_sort | cag repeat polymorphism of kcnn3 predicts sk3 channel function and cognitive performance in schizophrenia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377084/ https://www.ncbi.nlm.nih.gov/pubmed/21433290 http://dx.doi.org/10.1002/emmm.201100135 |
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