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Updated: Nov 23, 2025

Functional Characterization of Endogenously Expressed Human RYR1 Variants
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Functional Characterization of Endogenously Expressed Human RYR1 Variants

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Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation

Haikel Dridi1,2, Wei Wu3,4, Steven R Reiken1,2

  • 1Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia, University, New York, NY 10032, USA.

Human Molecular Genetics
|January 3, 2021
PubMed

Insights

Mutations in the lamin A/C gene (LMNA) cause disease by altering intracellular calcium (Ca2+) release channels (RyRs). This RyR remodeling leads to heart and muscle dysfunction, but can be improved with a novel drug.

Area of Science:

  • Cardiovascular Biology
  • Muscle Physiology
  • Genetic Diseases

Background:

  • Mutations in the lamin A/C gene (LMNA) cause laminopathies, including dilated cardiomyopathy and muscular dystrophy.
  • The precise role of calcium (Ca2+) dysregulation in LMNA-related diseases is not well understood.

Purpose of the Study:

  • To investigate the biochemical remodeling of intracellular Ca2+ release channels (RyRs) in LMNA mutation-associated diseases.
  • To explore the therapeutic potential of targeting RyRs in these conditions.

Main Methods:

  • Analysis of heart samples from human subjects with LMNA mutations.
  • Biochemical and functional assessment of RyR remodeling in the LmnaH222P/H222P mouse model.
  • Evaluation of a novel Rycal drug (S107) for its therapeutic effects.

Main Results:

  • Biochemical remodeling of RyRs, including altered phosphorylation and oxidation, was observed in human and murine hearts and muscles with LMNA mutations.
  • This RyR remodeling was linked to age-dependent cardiac and skeletal muscle dysfunction in mice.
  • Treatment with S107 ameliorated defective heart and muscle function by stabilizing RyRs.
  • Increased SMAD3 phosphorylation and NADPH oxidase activity contributed to RyR oxidation.

Conclusions:

  • RyR remodeling is a key factor in cardiomyopathy and skeletal muscle dysfunction resulting from LMNA mutations.
  • Targeting these Ca2+ channels represents a promising therapeutic strategy for laminopathies.

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