The RYR2-Encoded Ryanodine Receptor/Calcium Release Channel in Patients Diagnosed Previously With Either Catecholaminergic Polymorphic Ventricular Tachycardia or Genotype Negative, Exercise-Induced Long QT SyndromeA Comprehensive Open Reading Frame Mutational Analysis
Argelia Medeiros-Domingo, MD, PhD*,
Zahurul A. Bhuiyan, MD, PhD ,
David J. Tester, BS*,
Nynke Hofman, MSc,
Hennie Bikker, PhD,
J. Peter van Tintelen, MD, PhD¶,
Marcel M.A.M. Mannens, PhD,
Arthur A.M. Wilde, MD, PhD,|| and
Michael J. Ackerman, MD, PhD*, , ,*
* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
|| Department of Cardiology and Heart Failure Research Centre, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
¶ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Figure 1 Mutation Clustering in the RyR2
Mutations clustered in the cardiac ryanodine receptor (RyR2) are distributed in 3 "hot-spot" regions, called domains I (N-terminal), II (central), and III (channel region). AA = amino acid number estimated for each domain. Adapted from George et al. (7) and Yano et al. (6).
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Figure 2 RyR2 Channel Topology and Localization of Mutations and Polymorphisms
Linear topology of the cardiac ryanodine receptor (RyR2); putative pathogenic mutations (yellow circles) and polymorphisms (blue circles) found in this study cohort are shown in the approximate location. The number within the circle corresponds to the mutation number on Table 2. SR = sarcoplasmic reticulum.
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Figure 3 Prevalence of RYR2 Mutations by Subgroups
The yield from the entire RYR2 scan on this cohort is shown on the left. Bars on the right show the yield in the 3 different subgroups of this cohort. CPVT = catecholaminergic polymorphic ventricular tachycardia; LQTS = long QT syndrome.
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Figure 4 Possible Tiered Strategy for RYR2 Genetic Testing
Schematic representation of the 105 coding exons of the RYR2 gene. Colored boxes represent all of the exon-containing mutations reported to date; white boxes represent exons free of reported mutations. The tiered strategy was built on the basis of the number of mutations contained in each exon as shown by 3 different colors. The first tier included 16 exons; the second tier, 13 exons; and the third tier, 16 exons. Exons containing control variants were not included.
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Figure 5 Yield From RYR2 Mutational Analysis on the Basis of a Tiered Strategy
Retrospective analysis of the mutations detected in our cohort (purple bars) and in the world-wide compendium (orange bars) of mutations reported to date. The percentage of mutations that would be detected using the tiered strategy is shown.
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