Open Access Research

Alternative ion channel splicing in mesial temporal lobe epilepsy and Alzheimer's disease

Erin L Heinzen1, Woohyun Yoon1, Michael E Weale1, Arjune Sen2, Nicholas W Wood3, James R Burke4, Kathleen A Welsh-Bohmer4, Christine M Hulette4, Sanjay M Sisodiya2 and David B Goldstein1*

Author Affiliations

1 Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, Durham, NC 27710, USA

2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London WC1N 3BG, UK

3 Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK

4 Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC 27710, USA

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Genome Biology 2007, 8:R32  doi:10.1186/gb-2007-8-3-r32

Published: 7 March 2007

Abstract

Background

Alternative gene transcript splicing permits a single gene to produce multiple proteins with varied functions. Bioinformatic investigations have identified numerous splice variants, but whether these transcripts are translated to functional proteins and the physiological significance of these alternative proteins are largely unknown. Through direct identification of splice variants associated with disease states, we can begin to address these questions and to elucidate their roles in disease predisposition and pathophysiology. This work specifically sought to identify disease-associated alternative splicing patterns in ion channel genes by comprehensively screening affected brain tissue collected from patients with mesial temporal lobe epilepsy and Alzheimer's disease. New technology permitting the screening of alternative splice variants in microarray format was employed. Real time quantitative PCR was used to verify observed splice variant patterns.

Results

This work shows for the first time that two common neurological conditions are associated with extensive changes in gene splicing, with 25% and 12% of the genes considered having significant changes in splicing patterns associated with mesial temporal lobe epilepsy and Alzheimer's disease, respectively. Furthermore, these changes were found to exhibit unique and consistent patterns within the disease groups.

Conclusion

This work has identified a set of disease-associated, alternatively spliced gene products that represent high priorities for detailed functional investigations into how these changes impact the pathophysiology of mesial temporal lobe epilepsy and Alzheimer's disease.