Supplementary Materials

The PDF file includes:

• Materials and Methods
• Fig. S1. Pedigrees of families with non-CPVT–associated RyR2 mutations.
• Fig. S2. Non-CPVT–associated RyR2 mutations suppress caffeine-induced Ca²⁺ release.
• Fig. S3. Effects of mutations on the expression and function of RyR2.
• Fig. S4. The D4646A mutation suppresses Ca²⁺ activation of single RyR2 channels in lipid bilayers.
• Fig. S5. Generation and functional characterization of knock-in mouse model expressing the RyR2 mutation D4646A^+/−.
• Fig. S6. Effects of RyR2-D4646A^+/− on caffeine-promoted spontaneous Ca²⁺ release and depolarization-induced Ca²⁺ transients.
• Fig. S7. Effects of RyR2-D4646A^+/− on Ca²⁺ alternans and Ca²⁺ release refractoriness.
• Fig. S8. Effects of RyR2-D4646A^+/− on the I_to current, cardiac structure and fibrosis, L-type Ca²⁺ channel surface expression, and oxidative stress.
• Fig. S9. Effects of RyR2-D4646A^+/− on the expression of Ca²⁺ handling proteins, ion channels, and their associated proteins.
• Fig. S10. Effects of RyR2-D4646A^+/− on the expression of Ca²⁺ handling protein, ion channel, phosphatases, and kinases.
• Fig. S11. Effects of RyR2 mutations on Ca²⁺ transients and SR Ca²⁺ contents.
• Fig. S12. Electrical conduction in the RyR2-WT and D4646A^+/− hearts.
• Table S1. LOD scores for each family specified by RYR2 mutation.
• Table S2. Echocardiographic parameters of RyR2-WT and D4646A^+/− mutant mice.
• References (42–54)

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Other Supplementary Material for this manuscript includes the following:

• Data file S1 (Microsoft Excel format). Individual subject-level data.