TY - JOUR
T1 - LQT5 masquerading as LQT2
T2 - A dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current
AU - Nof, Eyal
AU - Barajas-Martinez, Hector
AU - Eldar, Michael
AU - Urrutia, Janire
AU - Caceres, Gabriel
AU - Rosenfeld, Gail
AU - Bar-Lev, David
AU - Feinberg, Micha
AU - Burashnikov, Elena
AU - Casis, Oscar
AU - Hu, Dan
AU - Glikson, Michael
AU - Antzelevitch, Charles
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Athlete
KW - Electrophysiology
KW - Long QT syndrome
UR - http://www.scopus.com/inward/record.url?scp=80053428955&partnerID=8YFLogxK
U2 - 10.1093/europace/eur184
DO - 10.1093/europace/eur184
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AN - SCOPUS:80053428955
SN - 1099-5129
VL - 13
SP - 1478
EP - 1483
JO - Europace
JF - Europace
IS - 10
ER -