LQT5 masquerading as LQT2: A dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current

Eyal Nof, Hector Barajas-Martinez, Michael Eldar, Janire Urrutia, Gabriel Caceres, Gail Rosenfeld, David Bar-Lev, Micha Feinberg, Elena Burashnikov, Oscar Casis, Dan Hu, Michael Glikson, Charles Antzelevitch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Aims: 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 IKs current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype.Methods and 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 IKr. Homozygous co-expression of the mutant with KCNH2 reduced IKr 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 IKr. Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in IKs.Conclusion: sOur 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 IKr. 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.

Original languageEnglish
Pages (from-to)1478-1483
Number of pages6
Issue number10
StatePublished - Oct 2011
Externally publishedYes


FundersFunder number
National Heart, Lung, and Blood InstituteR55HL047678


    • Arrhythmia
    • Athlete
    • Electrophysiology
    • Long QT syndrome


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