TY - JOUR
T1 - A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia
AU - Huffaker, Stephen J.
AU - Chen, Jingshan
AU - Nicodemus, Kristin K.
AU - Sambataro, Fabio
AU - Yang, Feng
AU - Mattay, Venkata
AU - Lipska, Barbara K.
AU - Hyde, Thomas M.
AU - Song, Jian
AU - Rujescu, Dan
AU - Giegling, Ina
AU - Mayilyan, Karine
AU - Proust, Morgan J.
AU - Soghoyan, Armen
AU - Caforio, Grazia
AU - Callicott, Joseph H.
AU - Bertolino, Alessandro
AU - Meyer-Lindenberg, Andreas
AU - Chang, Jay
AU - Ji, Yuanyuan
AU - Egan, Michael F.
AU - Goldberg, Terry E.
AU - Kleinman, Joel E.
AU - Lu, Bai
AU - Weinberger, Daniel R.
N1 - Funding Information:
We thank J. Hardy, J. Duckworth and P. Momeni for technical assistance with high G-C content sequencing. We also thank J. Hardy, D. Goldman, A. Law and W. Chen for their very helpful review of the manuscript. We thank R. Straub and M. Mayhew for their input on statistical genetics analysis, M. Barenboim for help with bioinformatics and M. Herman and S. Mitkus for their help with postmortem tissue. We are extremely grateful for the assistance of G. Liu and S. Chen in the cloning and sequencing of KCNH2-3.1. We also would like to thank H.-J. Möller, P. Muglia and coworkers at the Department of Psychiatry, Ludwig Maximilians University for their help with subject recruitment and evaluation. S.J. Huffaker was partially supported by the US National Institutes of Health/Cambridge University Health Science Scholars and Medical Scientist Training Programs. Recruitment of the individuals with schizophrenia at Ludwig Maximilians University was supported by GlaxoSmithKline. Human fetal tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland.
PY - 2009/5
Y1 - 2009/5
N2 - Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5′ complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K + current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.
AB - Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5′ complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K + current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.
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U2 - 10.1038/nm.1962
DO - 10.1038/nm.1962
M3 - Article
C2 - 19412172
AN - SCOPUS:66749174141
SN - 1078-8956
VL - 15
SP - 509
EP - 518
JO - Nature medicine
JF - Nature medicine
IS - 5
ER -