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Updated: May 26, 2026
An Electrochemiluminescence-Based Assay for MeCP2 Protein Variants
Published on: May 22, 2020
Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome
Mark D McCauley1, Tiannan Wang, Elise Mike
1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Rett syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG-binding protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2(Null/Y), also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2(Null/+), show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2(Null/Y) mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2(Null/Y) mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2(Null/Y) mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.
Insights
Sudden deaths in Rett syndrome may stem from cardiac issues. This study found abnormal heart rhythms linked to nervous system changes, suggesting phenytoin as a potential treatment to prevent fatal arrhythmias.
Area of Science:
- Neuroscience
- Cardiology
- Genetics
Background:
- Rett syndrome, a neurodevelopmental disorder caused by MECP2 mutations, is associated with unexplained sudden deaths.
- Cardiac dysfunction is hypothesized as a cause for these fatalities.
Purpose of the Study:
- To investigate the link between MECP2 mutations and cardiac abnormalities in Rett syndrome.
- To explore potential therapeutic targets for preventing cardiac arrhythmias.
Main Methods:
- Electrocardiogram (ECG) analysis in 379 individuals with Rett syndrome.
- Characterization of cardiac function in Mecp2-deficient mouse models (Mecp2(Null/Y) and Mecp2(Null/+)).
- Electrophysiological studies of cardiomyocytes and assessment of drug efficacy (beta-blockers and phenytoin).
Main Results:
- 18.5% of individuals with Rett syndrome exhibited prolonged corrected QT interval (QTc), indicating repolarization abnormalities.
- Mecp2-deficient mice showed prolonged QTc, increased susceptibility to ventricular tachycardia, and cardiac-related deaths.
- Neuronally mediated changes affecting cardiac electrical conduction were implicated.
- Phenytoin normalized persistent sodium current in cardiomyocytes and reduced QTc and ventricular tachycardia in mice.
Conclusions:
- Cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control due to MECP2 dysfunction.
- Increased persistent sodium current contributes to lethal cardiac arrhythmias.
- Targeting persistent sodium current with drugs like phenytoin may offer a more effective therapeutic strategy for preventing fatal arrhythmias in Rett syndrome.
