Development of a Patient-Specific p.D85N-Potassium Voltage-Gated Channel Subfamily E Member 1–Induced Pluripotent Stem Cell–Derived Cardiomyocyte Model for Drug-Induced Long QT Syndrome

Kim, Maengjo; Ye, Dan; Kim, C.S. John; Zhou, Wei; Tester, David J.; Giudicessi, John R.; Ackerman, Michael J.

doi:10.1161/circgen.120.003234

Cited by 7 publications

(1 citation statement)

References 25 publications

(50 reference statements)

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“…For our here investigated LQT5 mutations, too little clinical data on affected patients are available to conclusively determine whether the specific mutations cause sex differences in QT duration and arrhythmias or even estrous cycle–dependent changes in arrhythmic risk. However, for the common KCNE1 polymorphism pD85N, a sex-specific modulatory effect of the susceptibility to drug-induced LQTS has already been described with 17β-E2–mediated exaggeration of dofetilide-induced APD prolongation and increase in proarrhythmic early afterdepolarizations in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) ( 51 ), pointing toward a normal WT-like inhibitory 17β-E2 effect on Kv7.1/KCNE1_D85N and strongly supporting a role of KCNE1 variants in mediating (parts of) the observed sex differences in LQTS.…”

Section: Discussionmentioning

confidence: 99%

Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1

et al. 2023

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Estradiol (17 $ β $ -E2) is implicated in higher arrhythmia risk of women with congenital or acquired long-QT syndrome (LQTS) compared to men. However, the underlying mechanisms remain poorly understood, and little is known about the impact of LQTS-associated mutations. We show that 17 $ β $ -E2 inhibits the human cardiac Kv7.1/KCNE1 channel expressed in Xenopus oocytes. We find that the 17 $ β $ -E2 effect depends on the Kv7.1 to KCNE1 stoichiometry, and we reveal a critical function of the KCNE1 carboxyl terminus for the effect. LQTS-associated mutations in the KCNE1 carboxyl terminus show a range of responses to 17 $ β $ -E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 17 $ β $ -E2 inhibition of Kv7.1/KCNE1 and demonstrates mutation-dependent responses to 17 $ β $ -E2. These findings suggest that the 17 $ β $ -E2 effect on Kv7.1/KCNE1 might contribute to the higher arrhythmia risk of women, particularly in carriers with specific LQTS-associated mutations.

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Section: Discussionmentioning

confidence: 99%