INTRODUCTION AND OBJECTIVES: Catecholaminergic polymorphic ventricular 
tachycardia is a malignant disease, due to mutations in proteins controlling 
Ca(2+) homeostasis. While the phenotype is characterized by polymorphic 
ventricular arrhythmias under stress, supraventricular arrhythmias may occur and 
are not fully characterized.
METHODS: Twenty-five relatives from a Spanish family with several sudden deaths 
were evaluated with electrocardiogram, exercise testing, and optional 
epinephrine challenge. Selective RyR2 sequencing in an affected individual and 
cascade screening in the rest of the family was offered. The RyR2(R420Q) 
mutation was generated in HEK-293 cells using site-directed mutagenesis to 
conduct in vitro functional studies.
RESULTS: The exercise testing unmasked catecholaminergic polymorphic ventricular 
tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; 
negative predictive value = 93%), all of them carrying the heterozygous 
RyR2(R420Q) mutation, which was also present in the proband and a young girl 
without exercise testing, a 91% penetrance at the end of the follow-up. 
Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant 
post-effort U-waves were identified in patients. Upon permeabilization and in 
intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) 
release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) 
concentration, equivalent to the diastolic cytosolic concentration, the 
RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type 
cells.
CONCLUSIONS: The missense RyR2(R420Q) mutation was identified in the N-terminus 
of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is 
associated with sinus bradycardia, atrial and junctional arrhythmias, and giant 
U-waves. Collectively, functional heterologous expression studies suggest that 
the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function 
mutation depending on cytosolic intracellular Ca(2+) concentration.