Thorac Cardiovasc Surg 2006; 54 - PP_70
DOI: 10.1055/s-2006-925852

A combination of single nucleotide polymorphisms of the human cardiac ryanodine receptor is associated with arrhythmogenic right ventricular cardiomyopathy

H Milting 1, B Klauke 1, R Thieleczek 1, N Lukas 2, A Perrot 3, KJ Osterziel 3, S Peters 4, J Vogt 5, R Körfer 1, M Varsanyi 2
  • 1Herz- und Diabeteszentrum NRW, Klinik für Thorax- und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany
  • 2Ruhr-Universität Bochum, Institut für Physiologische Chemie I, Bochum, Germany
  • 3Charité-Universitätsmedizin Berlin/Kardiologie am Campus Buch & Virchow-Klinikum & Max Delbrück-Zentrum für Molekulare Medizin, Berlin, Germany
  • 4Klinikum Quedlinburg, Innere Medizin, Abteilung Kardiologie, Quedlinburg, Germany
  • 5Herz- und Diabeteszentrum NRW, Kardiologische Klinik, Bad Oeynhausen, Germany

Aims: Single nucleotide polymorphisms (SNPs) in the cardiac ryanodine receptor (RYR2) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). The molecular mechanisms, however, by which genetic modifications lead to this cardiomyopathy, are still not well understood.

Methods: 85 ARVC patients were screened for mutations of all 105 RYR2-exons. We identified two SNPs in exon 37 of the human RYR2-gene leading to amino-acid exchanges G1885E and G1886S, respectively. Single channel measurements were carried out with isolated RyR2-channels purified from two explanted hearts of ARVC patients.

Results: Both SNPs were found in 3 out of 85 ARVC patients in a composite heterozygous fashion but not in 64 patients with dilated cardiomyopathy (DCM) or 463 blood donors. Either one of the two SNPs on a single allele was identified to a similar extend in further 7 ARVC patients as well as in 11 out of the DCM-patients and in 64 out of the blood donors. The SNP leading to G1886S may create a protein kinase C phosphorylation site in the human RyR2. Single channel recordings at pCa 4.3 revealed four subconductance-states for the RyR2 composite heterozygous genotype and a single open state for the wild-type RyR2. At pCa 7.7, the lowest subconductance state of the RyR2 channel of composite carriers of both SNPs persisted with an enhanced open probability (Po=0.57±0.17) indicating a leaky channel.

Conclusion: A RyR2 channel leak under diastolic conditions could cause SR-Ca2+ depletion leading to arrhythmogenesis and heart failure.