title: Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.
abstract: BACKGROUND
  Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]).
  
  
  RESULTS
  In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders.
  
  
  CONCLUSIONS
  Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Laitinen
authors.forename: K M
authors.initials: KM
authors.lastname: Brown
authors.forename: K
authors.initials: K
authors.lastname: Piippo
authors.forename: H
authors.initials: H
authors.lastname: Swan
authors.forename: J M
authors.initials: JM
authors.lastname: Devaney
authors.forename: B
authors.initials: B
authors.lastname: Brahmbhatt
authors.forename: E A
authors.initials: EA
authors.lastname: Donarum
authors.forename: M
authors.initials: M
authors.lastname: Marino
authors.forename: N
authors.initials: N
authors.lastname: Tiso
authors.forename: M
authors.initials: M
authors.lastname: Viitasalo
authors.forename: L
authors.initials: L
authors.lastname: Toivonen
authors.forename: D A
authors.initials: DA
authors.lastname: Stephan
authors.forename: K
authors.initials: K
authors.lastname: Kontula
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005387:Finland; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D010375:Pedigree; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000473:pathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA