Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy
Heterozygosity for missense mutations in 1 of 3 seemingly redundant calmodulin-encoding (CALM-encoding) genes can cause life-threatening arrhythmias, suggesting that small fractions of mutant CALM protein suffice to cause a severe phenotype. However, the exact molar ratios of wild-type to mutant CALM protein in calmodulinopathy hearts remain unknown. The aim of the present study was to quantitate mutant versus wild-type CALM transcript and protein levels in hearts of knockin mice harboring the p.N98S mutation in the Calm1 gene. We found that the transcripts from the mutant Calm1 allele were the least abundantly expressed Calm transcripts in both hetero- and homozygous mutant hearts, while mutant hearts accumulated high levels of N98S-CALM protein in a Calm1N98S allele dosage-dependent manner, exceeding those of wild-type CALM protein. We further show that the severity of the electrophysiological phenotype incrementally increased with the graded increase in the mutant/wild-type CALM protein expression ratio seen in homozygous versus heterozygous mutant mice. We finally show a decrease in N98S-CALM protein degradation, suggesting that mutant CALM stabilization contributed to its enrichment in the heart. Our results support what we believe to be a novel mechanism by which a mutation in a single Calm gene can give rise to a severe phenotype.
Authors
- Kai‐Chien Yang (ORCID: https://orcid.org/0000-0002-9128-9166)
- Tzu‐Ching Meng (ORCID: https://orcid.org/0000-0001-7693-2021)
- Suh‐Yuen Liang (ORCID: https://orcid.org/0000-0001-8918-7112)
- Peng‐Sheng Chen (ORCID: https://orcid.org/0000-0002-4150-5836)
- Michael Rubart (ORCID: https://orcid.org/0000-0002-7386-6943)
- Susan Ofner (ORCID: https://orcid.org/0000-0001-8107-7859)
- Shuai Guo (ORCID: https://orcid.org/0000-0002-9368-0548)
- Wei‐Chung Tsai
- Shu‐Yu Lin (ORCID: https://orcid.org/0000-0003-3054-3332)
- Chiu-Fen Yang
- Xiaochun Li
- Wen-Chin Tsai
Institutions
- Cedars-Sinai Medical Center (US)
- Kaohsiung Medical University (TW)
- National Taiwan University (TW)
- Tzu Chi Foundation (TW)
- Kaohsiung Medical University Chung-Ho Memorial Hospital (TW)
- Riley Hospital for Children (US)
- Institute of Biological Chemistry, Academia Sinica (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Hualien Tzu Chi Medical Center (TW)
- Cedars-Sinai Smidt Heart Institute (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Academia Sinica (TW)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1172/jci.insight.185524
- Primary Topic
- Cardiovascular Function and Risk Factors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Foundation for the National Institutes of Health
- American Heart Association
- Cedars-Sinai Medical Center
- Academia Sinica
- Kaohsiung Medical University
- National Health Research Institutes
- Buddhist Tzu Chi Medical Foundation
- Kaohsiung Medical University Chung-Ho Memorial Hospital
- National Science and Technology Council
- National Institutes of Health