title: Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia.
abstract: OBJECTIVE
  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.
authors.affiliation: Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Domingo
authors.affiliation: Inserm, U769, Université de Paris Sud, IFR141, LabEx Lermit, Châtenay-Malabry, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Neco
authors.affiliation: Grupo de Investigación acreditado de Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Fernández-Pons
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Spyros
authors.initials: S
authors.lastname: Zissimopoulos
authors.affiliation: Servicio de Histopatología, Instituto de Medicina Legal, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Molina
authors.affiliation: Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Olagüe
authors.affiliation: Servicio de Histopatología, Instituto Nacional de Toxicología y Ciencias Forenses, Madrid, Spain.
authors.forename: M Paz
authors.initials: MP
authors.lastname: Suárez-Mier
authors.affiliation: Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Lai
authors.affiliation: Inserm, U769, Université de Paris Sud, IFR141, LabEx Lermit, Châtenay-Malabry, France.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gómez
authors.affiliation: Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain. Electronic address: zorio_est@gva.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Zorio
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D057809:HEK293 Cells / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA
keywords: Calcio; Calcium; Canales iónicos; Electrocardiografía; Electrocardiography; Genetics; Genética; Ion channels; Muerte súbita; Receptor 2 de rianodina; Ryanodine receptor-2; Sudden death