title: LQT5 masquerading as LQT2: a dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current.
abstract: OBJECTIVE
  KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of-function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of I(Ks) current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype.
  
  
  RESULTS
  An 11-year old competitive athlete presented with mild bradycardia and a QTc interval of 470 ms. An LQT2 phenotype, consisting of low-voltage bifid T waves, was evident in the right precordial electrocardiogram leads. During the tachycardia phase following adenosine, QTc increased to 620 ms. Genetic analysis revealed a rare heterozygous polymorphism in KCNE1 predicting the substitution of asparagine for aspartic acid at position 85 of minK (D85N). Patch clamp experiments showed that KCNE1-D85N, when co-expressed with KCNH2 in TSA201 cells, significantly reduced I(Kr). Homozygous co-expression of the mutant with KCNH2 reduced I(Kr) tail current by 85%, whereas heterozygous co-expression reduced the current by 52%, demonstrating for the first time a dominant-negative effect of D85N to reduce I(Kr). Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in I(Ks).
  
  
  CONCLUSIONS
  Our results suggest that a rare polymorphism KCNE1-D85N underlies the development of an LQT2 phenotype in this young athlete by interacting with KCNH2 to cause a dominant-negative effect to reduce I(Kr). Our data provide further evidence in support of the promiscuity of potassium channel β subunits in modulating the function of multiple potassium channels leading to a diversity of clinical phenotypes.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Nof
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Michael
authors.initials: M
authors.lastname: Eldar
authors.forename: Janire
authors.initials: J
authors.lastname: Urrutia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Caceres
authors.forename: Gail
authors.initials: G
authors.lastname: Rosenfeld
authors.forename: David
authors.initials: D
authors.lastname: Bar-Lev
authors.forename: Micha
authors.initials: M
authors.lastname: Feinberg
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: Glikson
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D056352:Athletes; D001919:Bradycardia / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D002648:Child; D003937:Diagnosis, Differential; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000145:classification* / Q000175:diagnosis* / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated