Human calmodulin mutations cause arrhythmia and affect neuronal function in C. elegans

Helene H Jensen, Magnus T Frantzen, Jonas L Wesseltoft, Ana-Octavia Busuioc, Katrine V Møller, Malene Brohus, Palle R Duun, Mette Nyegaard, Michael T Overgaard, Anders Olsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

2 Citations (Scopus)
17 Downloads (Pure)


In humans, mutations in calmodulin cause cardiac arrhythmia. These mutations disrupt the ability of calmodulin to sense calcium concentrations and correctly regulate two central calcium channels, together obstructing heart rhythm. This correlation is well established, but also surprising since calmodulin is expressed in all tissues and interacts with hundreds of proteins. Until now, most studies have focused on cardiac cell function and regulation of specific cardiac targets, and thus potential other effects of these mutations have largely been unexplored. Here, we introduce the nematode Caenorhabditis elegans as an in vivo model to study effects of three human calmodulin mutations with different impairment on calcium binding. We find that arrhythmic effects of the calmodulin mutations N54I and D96V can be recapitulated in disruption of two rhythmic behaviors, pharynx pumping and defecation motor program. Interestingly, we also find that these mutations affect neuronal function, but in different ways. Whereas D96V sensitizes signaling at the neuromuscular junction, N54I has a protective effect. The mutation N98S did not affect rhythmic behavior, but impaired chemosensing. Therefore, pathogenic calmodulin mutations act through different mechanisms in rhythmic behavior and neuronal function in C. elegans, emphasizing the strength of using live multicellular models. Finally, our results support the hypothesis that human calmodulin mutations could also contribute to neurological diseases.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number12
Pages (from-to)2068-2083
Number of pages16
Publication statusPublished - 12 Jun 2023

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press.


  • Animals
  • Arrhythmias, Cardiac/metabolism
  • Caenorhabditis elegans Proteins/genetics
  • Caenorhabditis elegans/genetics
  • Calcium/metabolism
  • Calmodulin/genetics
  • Humans
  • Mutation


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