Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2

Francisco J. Alvarado, J. Martijn Bos, Zhiguang Yuchi, Carmen R. Valdivia, Jonathan J. Hernandez, Yan Ting Zhao, Dawn S. Henderlong, Yan Chen, Talia R. Booher, Cherisse A. Marcou, Filip Van Petegem, Michael John Ackerman, Hector H. Valdivia

Research output: Contribution to journalArticle

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Abstract

Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

Original languageEnglish (US)
JournalJCI insight
Volume5
DOIs
StatePublished - Mar 5 2019

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Ryanodine Receptor Calcium Release Channel
Cardiomegaly
Cardiac Arrhythmias
Mutation
Hypertrophic Cardiomyopathy
Calmodulin
Phenotype
Genotype
Age of Onset
Hypertrophy

Keywords

  • Calcium
  • Cardiology
  • Cardiovascular disease
  • Excitation contraction coupling

Cite this

Alvarado, F. J., Bos, J. M., Yuchi, Z., Valdivia, C. R., Hernandez, J. J., Zhao, Y. T., ... Valdivia, H. H. (2019). Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2. JCI insight, 5. https://doi.org/10.1172/jci.insight.126544

Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2. / Alvarado, Francisco J.; Bos, J. Martijn; Yuchi, Zhiguang; Valdivia, Carmen R.; Hernandez, Jonathan J.; Zhao, Yan Ting; Henderlong, Dawn S.; Chen, Yan; Booher, Talia R.; Marcou, Cherisse A.; Van Petegem, Filip; Ackerman, Michael John; Valdivia, Hector H.

In: JCI insight, Vol. 5, 05.03.2019.

Research output: Contribution to journalArticle

Alvarado, FJ, Bos, JM, Yuchi, Z, Valdivia, CR, Hernandez, JJ, Zhao, YT, Henderlong, DS, Chen, Y, Booher, TR, Marcou, CA, Van Petegem, F, Ackerman, MJ & Valdivia, HH 2019, 'Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2', JCI insight, vol. 5. https://doi.org/10.1172/jci.insight.126544
Alvarado, Francisco J. ; Bos, J. Martijn ; Yuchi, Zhiguang ; Valdivia, Carmen R. ; Hernandez, Jonathan J. ; Zhao, Yan Ting ; Henderlong, Dawn S. ; Chen, Yan ; Booher, Talia R. ; Marcou, Cherisse A. ; Van Petegem, Filip ; Ackerman, Michael John ; Valdivia, Hector H. / Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2. In: JCI insight. 2019 ; Vol. 5.
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AU - Bos, J. Martijn

AU - Yuchi, Zhiguang

AU - Valdivia, Carmen R.

AU - Hernandez, Jonathan J.

AU - Zhao, Yan Ting

AU - Henderlong, Dawn S.

AU - Chen, Yan

AU - Booher, Talia R.

AU - Marcou, Cherisse A.

AU - Van Petegem, Filip

AU - Ackerman, Michael John

AU - Valdivia, Hector H.

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N2 - Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

AB - Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

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