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Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular

Hendrik Milting1, Nina Lukas, Bärbel Klauke

  • 1Herz- und Diabeteszentrum NRW, Klinik der Ruhr-Universität Bochum, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Georgstr. 11, 32545 Bad Oeynhausen, Germany. hmilting@hdz-nrw.de

Cardiovascular Research
|June 14, 2006
PubMed
Abstract

Insights

New RYR2 gene variants were found in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. These RYR2 gene variants may cause a leaky channel, leading to heart failure and arrhythmias in some ARVC patients.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Cardiac Electrophysiology

Background:

  • Mutations in the cardiac ryanodine receptor (RYR2) gene are implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC).
  • The precise molecular mechanisms linking RYR2 genetic alterations to ARVC pathogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate novel RYR2 gene mutations associated with arrhythmogenic right ventricular cardiomyopathy.
  • To elucidate the functional consequences of identified RYR2 variants on channel behavior and their potential role in ARVC.

Main Methods:

  • Screening of ARVC patients for RYR2 gene mutations using denaturing HPLC and DNA sequencing.
  • Purification and single-channel functional measurements of RyR2 channels from explanted hearts of ARVC patients.
  • Genotyping of identified single nucleotide polymorphisms (SNPs) in ARVC, dilated cardiomyopathy (DCM), and control cohorts.

Main Results:

  • No previously reported RYR2 mutations were identified in the ARVC cohort.
  • Two novel single nucleotide polymorphisms (SNPs) in RYR2 exon 37, leading to G1885E and G1886S amino acid exchanges, were found exclusively in a composite heterozygous fashion (genotype T4) in 3 out of 85 ARVC patients.
  • Genotype T4 was significantly associated with ARVC (p<0.05) but not with DCM or controls. The G1886S SNP may create a protein kinase C phosphorylation site. Single-channel recordings revealed altered conductance states and a "leaky" channel phenotype at diastolic conditions (pCa7.7) for genotype T4 RyR2.

Conclusions:

  • A leaky cardiac ryanodine receptor (RYR2) channel under diastolic conditions, caused by the combined RYR2 SNPs (genotype T4), may lead to sarcoplasmic reticulum calcium depletion.
  • This calcium dysregulation can precipitate arrhythmogenesis and heart failure in a subset of ARVC patients with genotype T4.
  • Alterations in RYR2 subunit composition due to combined SNP expression modify the functional behavior of the tetrameric channel complex, contributing to ARVC pathophysiology.

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