Editors' ChoiceSchizophrenia

Channeling Cognitive Performance

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Science Translational Medicine  13 Jul 2011:
Vol. 3, Issue 91, pp. 91ec110
DOI: 10.1126/scitranslmed.3002851

“Water, water everywhere, but not a drop to drink,” is a phrase that some might use to characterize current genetic association studies of human disease. Our ability to detect genetic polymorphisms associated with disease has increased exponentially over the past 10 years. In most cases, we have little understanding of the molecular function of these gene variants. Thus, translation of human genetic findings into new therapeutic agents has lagged, although we should be poised to drink from this cup of knowledge soon. In a recent study, Grube et al. provide an elegant example of gene-to-function progress, showing that a genetic variant associated with schizophrenia alters the function of a potassium channel and affects cognitive performance in schizophrenia patients.

The authors studied 1074 patients with schizophrenia who had been genotyped at a CAG repeat in the SK3 gene, which encodes a calcium-activated potassium channel expressed in the brain. This CAG polymorphism has previously been associated with schizophrenia in genetic studies. Exploring clinical variables, the authors found a strong association between a larger number of CAG repeats and improved cognitive performance. The authors generated human cell lines expressing SK3 with different CAG repeat lengths; increased CAG repeat number resulted in decreased function of the SK3 channel. Additionally, the authors over-expressed SK3 in mice, which resulted in decreased higher cognitive function but unaffected basic behavioral traits.

Taken together, these data suggest that longer CAG repeats in SK3 decrease function of the ion channel, resulting in increased cognitive ability, through a mechanism that is not yet clear. The genetic study of phenotypes within disease, in this case cognitive performance, enabled translational experiments in human cell lines and model organisms, providing a fascinating window into the function of this genetic variant and suggesting that blockers of the SK3 channel should be tested as possible therapeutic agents for cognitive dysfunction in schizophrenia.

S. Grube et al., A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO Mol. Med. 3, 309–319 (2011). [Abstract]

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