Evidence for defective N-terminal inter-subunit interactions due to RyR1 (top) and RyR2 (bottom) pathogenic mutations within the β8-β9 and β23-β24 loops (ARVD2: arrhythmogenic right ventricular dysplasia 2, CCD: central core disease, CPVT: catecholaminergic polymorphic ventricular tachycardia, MH: malignant hyperthermia, SUD: sudden unexplained death). The gene discussed is RYR1; the disease is Malignant hyperthermia.