Journal Article

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

Xiaoli Zhong, Jinrong R. Liu, John W. Kyle, Dorothy A. Hanck and William S. Agnew

in Human Molecular Genetics

Volume 15, issue 9, pages 1497-1512
Published in print May 2006 | ISSN: 0964-6906
Published online March 2006 | e-ISSN: 1460-2083 | DOI:

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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.

Journal Article.  11518 words.  Illustrated.

Subjects: Genetics and Genomics

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