Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels
Open Access
- 1 January 2018
- journal article
- research article
- Published by Informa UK Limited in Channels
- Vol. 12 (1), 388-402
- https://doi.org/10.1080/19336950.2018.1546518
Abstract
Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk. Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of-function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes.Keywords
Funding Information
- Austrian Science Fund (W1101)
- Austrian Science Fund (P27809)
This publication has 45 references indexed in Scilit:
- Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronismNature Genetics, 2013
- Structural determinants of CaV1.3 L-type calcium channel gatingChannels, 2012
- Pathophysiological Role of Omega Pore Current in ChannelopathiesFrontiers in Pharmacology, 2012
- Functional Properties of a Newly Identified C-terminal Splice Variant of Cav1.3 L-type Ca2+ ChannelsPublished by Elsevier BV ,2011
- Functional Characterization of Alternative Splicing in the C Terminus of L-type CaV1.3 ChannelsPublished by Elsevier BV ,2011
- Voltage-sensor mutations in channelopathies of skeletal muscleThe Journal of Physiology, 2010
- Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channelsPflügers Archiv - European Journal of Physiology, 2010
- Enzyme-inhibitor-like tuning of Ca2+ channel connectivity with calmodulinNature, 2010
- Modulation of Voltage- and Ca2+-dependent Gating of CaV1.3 L-type Calcium Channels by Alternative Splicing of a C-terminal Regulatory DomainPublished by Elsevier BV ,2008
- Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environmentNature, 2007