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

• Published in: Europace (London, England) England), 2011-10, Vol.13 (10), p.1478-1483
• Main Authors: Nof, Eyal, Barajas-Martinez, Hector, Eldar, Michael, Urrutia, Janire, Caceres, Gabriel, Rosenfeld, Gail, Bar-Lev, David, Feinberg, Micha, Burashnikov, Elena, Casis, Oscar, Hu, Dan, Glikson, Michael, Antzelevitch, Charles
• Format: Article
• Language: English
• Subjects: Athletes; Bradycardia - diagnosis; Bradycardia - etiology; Bradycardia - physiopathology; Child; Diagnosis, Differential; Electrocardiography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - genetics; Female; Humans; Long QT Syndrome - classification; Long QT Syndrome - diagnosis; Long QT Syndrome - physiopathology; Phenotype; Polymorphism, Single Nucleotide - genetics; Potassium Channels, Voltage-Gated - genetics
• ISSN: 1099-5129; 1532-2092
• DOI: 10.1093/europace/eur184

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 I Ks 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 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.