Dataset Information

A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

ABSTRACT: Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current I_Ks. While mutant LQT5 KCNE1 variants are known to inhibit I_Ks amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged I_Ks amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of I_Ks channels minimizes the inhibitory effects of LQT5 KCNE1 variants on I_Ks amplitudes, while current deactivation is accelerated. Such changes recapitulate I_Ks properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the I_Ks ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the I_Ks channel complex that regulates I_Ks function in cardiomyocytes and modifies the development of the LQT5 phenotype.

SUBMITTER: Deri S

PROVIDER: S-EPMC9782992 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

Déri Szilvia S Hartai Teodóra T Virág László L Jost Norbert N Labro Alain J AJ Varró András A Baczkó István I Nattel Stanley S Ördög Balázs B

Pharmaceuticals (Basel, Switzerland) 20221213 12

Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current I<sub>Ks</sub>. While mutant LQT5 KCNE1 variants are known to inhibit I<sub>Ks</sub> amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unc ...[more]

PMID: 36559002

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Project description:Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations.Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) were compared between 388 unrelated "definite" (clinical diagnostic score >or=4 and/or QTc >or=480 ms) cases of LQTS and >1300 healthy controls for each gene. From these data, estimated predictive values (percent of mutations found in definite cases that would cause LQTS) were determined according to mutation type and location. Mutations were 10 times more common in cases than controls (0.58 per case versus 0.06 per control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Nonmissense mutations have an estimated predictive value >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from approximately 1:1 in the SCN5A interdomain linker to infinity in the pore, transmembrane, and linker in KCNH2. These correspond to estimated predictive values ranging from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. The estimated predictive value is also high in the linker, pore, transmembrane, and C terminus of KCNQ1 and the transmembrane/linker of SCN5A.Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specificshould be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.

Dataset Information

A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

Publications

A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

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