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Human Molecular Genetics Advance Access originally published online on March 24, 2006
Human Molecular Genetics 2006 15(9):1497-1512; doi:10.1093/hmg/ddl068
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies

Xiaoli Zhong1, Jinrong R. Liu3, John W. Kyle3, Dorothy A. Hanck3 and William S. Agnew1,2,*

1Department of Physiology and 2Department of Neuroscience, Johns Hopkins University School of Medicine and 3Department of Medicine, University of Chicago School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA

* To whom correspondence should be addressed. Tel: +1 4106141505; Fax: +1 4106148331; Email: wsagnew{at}jhmi.edu

Received January 13, 2006; Accepted March 16, 2006

Highly alternatively spliced genes may provide complex targets for disease mutations. Structural changes created by missense mutations may differentially affect the activity of alternative gene products, whereas missense, silent and non-coding mutations may alter developmental regulation of splice variant expression. CACNA1H is a human gene encoding Cav3.2 low-voltage-activated, T-type calcium channels associated with bursting behavior in neurons and has been linked to more than 30 mutations apparently predisposing to childhood absence epilepsy (CAE) and other idiopathic generalized epilepsies (IGEs). Biophysical properties, including the effects of missense mutations, have been evaluated previously for a single splice form of Cav3.2 expressed in transformed cell lines. We here show that CACNA1H is alternatively spliced at 12–14 sites, capable of generating both functional and non-functional transcripts. Variable cytoplasmic and extracellular protein domains point to likely differences in gating behavior, sensitivity to neuromodulation and interactions with extracellular matrix. Biophysical profiles of selected physiological Cav3.2 forms reveal variations in kinetics and steady-state gating parameters, most likely to affect membrane firing. These were comparable to or larger than changes reported for previously studied mutations. Missense CAE and IGE mutations were clustered near segments associated with anomalous splicing. Missense and silent mutations were found to destroy, create or change the regulatory specificity of predicted exonic splicing enhancer sequences that may control splicing regulation. We discuss a paradigm for CACNA1H expression of Cav3.2 subunits, which may influence future basic and clinical studies.


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