Advertisement

ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/jci.insight.185524

Cardiac enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy

Wen-Chin Tsai,1 Chiu-Fen Yang,1 Shu-Yu Lin,2 Suh-Yuen Liang,3 Wei-Chung Tsai,4 Shuai Guo,5 Xiaochun Li,6 Susan Ofner,6 Kai-Chien Yang,7 Tzu-Ching Meng,2 Peng-Sheng Chen,8 and Michael Rubart5

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Tsai, W. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Yang, C. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Lin, S. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Liang, S. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Tsai, W. in: PubMed | Google Scholar |

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Guo, S. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Li, X. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Ofner, S. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Yang, K. in: PubMed | Google Scholar |

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Meng, T. in: PubMed | Google Scholar

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Chen, P. in: PubMed | Google Scholar |

1Department of Cardiology, Cardiovascular Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

3Bioinformatics Core Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

4Division of Cardiology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, United States of America

6Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, United States of America

7Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan

8Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Rubart, M. in: PubMed | Google Scholar

Published July 24, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.185524.
Copyright © 2025, Tsai et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 24, 2025 - Version history
View PDF
Abstract

Heterozygosity for missense mutations in one of 3 seemingly redundant calmodulin (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 wildtype to mutant CALM protein in calmodulinopathy hearts remain unknown. The aim of the present study was to quantitate mutant versus wildtype CALM transcript and protein levels in hearts of knock-in 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 accumulate high levels of N98S-CALM protein in a Calm1N98S allele dosage-dependent manner, exceeding those of wildtype CALM protein. We further show that the severity of the electrophysiological phenotype incrementally increases with the graded increase in the mutant-to-wildtype 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.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Supplemental Data

Version history
  • Version 1 (July 24, 2025): In-Press Preview
Advertisement
Advertisement