De novo CACNA1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism.

Journal Article (Journal Article;Review)

The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca2+ channel blockers as a potential therapeutic option.

Full Text

Duke Authors

Cited Authors

  • Ortner, NJ; Kaserer, T; Copeland, JN; Striessnig, J

Published Date

  • July 2020

Published In

Volume / Issue

  • 472 / 7

Start / End Page

  • 755 - 773

PubMed ID

  • 32583268

Pubmed Central ID

  • PMC7351864

Electronic International Standard Serial Number (EISSN)

  • 1432-2013

Digital Object Identifier (DOI)

  • 10.1007/s00424-020-02418-w


  • eng

Conference Location

  • Germany