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Alternative Exon Effect on Phenotype of Cav1.2 Channelopathy: Implications in Timothy Syndrome

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Pathologies of Calcium Channels

Abstract

Timothy Syndrome is a multiorgan disorder that results from de novo, gain-of-function mutations within the voltage-gated Cav1.2 calcium channel. While G406R mutation occurs within exon 8, G402S and G406R are located in the mutually exclusive exon 8a. All three mutations similarly produced a drastic slowdown of channel inactivation. Excessive Ca2+ currents flowing through the Cav1.2 channels in different tissues underlie pathologies such as arrhythmia, dysregulation of functions in the endocrine and immune systems, autism spectral disorder, and other developmental defects such as syndactyly. Here, we discuss the diverse patterns and regulation of alternative splicing of the Cav1.2 channels, the functional impacts of the TS mutations on channel properties to relate to clinical features, and the possible therapeutic approaches in the future.

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Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, Singapore, Singapore

    Hua Huang & Tuck Wah Soong

  2. Department of Physiology, Nanjing Medical University, Nanjing, China

    Juejin Wang

  3. NUS Graduate School for Integrative Sciences and Engineering, singapore, singapore

    Tuck Wah Soong

  4. Neurobiology/Ageing Programme, National University of Singapore, Singapore, Singapore

    Tuck Wah Soong

  5. National Neuroscience Institute, Singapore, Singapore

    Tuck Wah Soong

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  1. Hua Huang
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  2. Juejin Wang
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Correspondence to Tuck Wah Soong .

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  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

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Huang, H., Wang, J., Soong, T.W. (2014). Alternative Exon Effect on Phenotype of Cav1.2 Channelopathy: Implications in Timothy Syndrome. In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_11

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