title: Biophysical and molecular characterization of a novel de novo KCNJ2 mutation associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry.
abstract: BACKGROUND
  Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1 or IKir2.1), have been identified in Andersen-Tawil syndrome. Andersen-Tawil syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia.
  
  
  RESULTS
  Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in KCNJ2. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human KCNJ2 cDNA (WT-KCNJ2) yielded robust IKir2.1 but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P-KCNJ2 (heterozygous expression) yielded a markedly reduced inward IKir2.1 compared with WT alone (-36.5±9.8 pA/pF versus -143.5±11.4 pA/pF, n=8 for both, P<0.001, respectively, at -90 mV), indicating a strong dominant negative effect of the mutant. The outward component of IKir2.1 measured at -50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both, P<0.001, respectively). Immunocytochemical analysis indicates that impaired trafficking of R260P-KCNJ2 channels.
  
  
  CONCLUSIONS
  We report a novel de novo KCNJ2 mutation associated with classic phenotypic features of Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of IK1 secondary to a trafficking defect.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ontiveros
authors.forename: Gabriel
authors.initials: G
authors.lastname: Caceres
authors.forename: Mayurika
authors.initials: M
authors.lastname: Desai
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Jorge
authors.initials: J
authors.lastname: Scaglione
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D050030:Andersen Syndrome / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D001483:Base Sequence; D055592:Biophysical Phenomena; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005424:Flecainide / Q000627:therapeutic use; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D014463:Ultrasonography; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D005424:Flecainide