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

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

Research output: Research - peer-reviewArticle

Abstract

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.

LanguageEnglish (US)
Pages1497-1512
Number of pages16
JournalHuman Molecular Genetics
Volume15
Issue number9
DOIs
StatePublished - May 2006

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Alternative Splicing
Mutation
Genes
human CACNA1H protein
Idiopathic Generalized Epilepsy
Missense Mutation
Absence Epilepsy
T-Type Calcium Channels
Transformed Cell Line
Recombinant DNA
Extracellular Matrix
Neurons
Membranes
Protein Domains
Silent Mutation
Clinical Studies

ASJC Scopus subject areas

  • Genetics

Cite this

A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. / Zhong, Xiaoli; Liu, Jinrong R.; Kyle, John W.; Hanck, Dorothy A.; Agnew, William S.

In: Human Molecular Genetics, Vol. 15, No. 9, 05.2006, p. 1497-1512.

Research output: Research - peer-reviewArticle

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