The genetic basis of long QT and short QT syndromes: A mutation update

Hedley, Paula L.; Jørgensen, Poul; Schlamowitz, Sarah; Wangari, Romilda; Moolman‐Smook, Johanna C.; Brink, Paul A.; Kanters, Jørgen K.; Corfield, Valerie A.; Christiansen, Michael

doi:10.1002/humu.21106

Cited by 392 publications

(323 citation statements)

References 424 publications

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“…Here we provide evidence that KCNE1, as a β-subunit, alters the function of I Ks by modulating the interaction between PIP 2 and the heteromeric ion channel complex. Knowledge of the molecular mechanisms of channel modulation by KCNE1 is of great importance as at least 36 LQT-associated mutations reside within KCNE1 (7)(8)(9).…”

mentioning

confidence: 99%

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Li¹,

Zaydman²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

136

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Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is necessary for the function of various ion channels. The potassium channel, I Ks , is important for cardiac repolarization and requires PIP 2 to activate. Here we show that the auxiliary subunit of I Ks , KCNE1, increases PIP 2 sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP 2 levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP 2 sensitivity. Long QT syndrome associated mutations of this site lower PIP 2 affinity, resulting in reduced current. Application of exogenous PIP 2 to these mutants restores wild-type channel activity. These results reveal a vital role of PIP 2 for KCNE1 modulation of I Ks channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.K CNQ1 α-subunits coassemble with KCNE1 β-subunits to form the cardiac slow-delayed rectifier channel, I Ks , which conducts a potassium current that is important for the termination of the cardiac action potential. Although exogenous expression of KCNQ1 alone is sufficient to produce a voltage-gated channel, coexpression of KCNE1 with KCNQ1 leads to changes in current properties to resemble the physiologically important cardiac I Ks current ( Fig. 1A) (1, 2). These changes include increased current amplitude, shift of the voltage dependence of activation toward more positive potentials, slowed activation and deactivation kinetics, and suppressed inactivation, all of which are essential for the physiological role of I Ks (3). After many years of investigation, it is still poorly understood how the KCNE1 peptide exerts such a dramatic effect on the I Ks current. Loss-offunction mutations in I Ks lead to delayed cardiac cell repolarization that manifests clinically as long QT (LQT) syndrome. Patients with LQT syndrome are predisposed to ventricular arrhythmia and suffer from syncope and a high risk of sudden cardiac death. At present, the molecular mechanisms of disease pathogenesis are still unknown for many LQT-associated mutations in I Ks .Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is a minor acidic membrane lipid found primarily in the inner leaflet of the plasma membrane. PIP 2 has been shown to be a necessary cofactor for a wide variety of ion channels, e.g., voltage-gated K þ and Ca 2þ channels, transient receptor potential channels, inward rectifying K þ channels, and epithelial Na þ channels (4). Recently, I Ks has been shown to require PIP 2 for channel activity, and several LQTassociated mutations located in KCNQ1 have been suggested to decrease the PIP 2 affinity of I Ks (5, 6). Here we provide evidence that KCNE1, as a β-subunit, alters the function of I Ks by modulating the interaction between PIP 2 and the heteromeric ion channel complex. Knowledge of the molecular mechanisms of channel modulation by KCNE1 is of great importance as at least 36 LQT-associated muta...

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mentioning

confidence: 99%

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Li¹,

Zaydman²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

136

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“…KCNH2 c.2682_2685dup p.(Asp896Hisfs*25) is located in the 3′ end of exon 11 and within a few base pairs reach of 3 other frameshift variants previously reported in patients with LQTS 19, 20, 21…”

Section: Resultsmentioning

confidence: 91%

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

Gibbs

Thalamus

Tveten

et al. 2018

JAHA

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BackgroundCongenital long‐QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the corrected QT interval (QTc) on an ECG. The aim of the present study was to estimate the prevalence of pathogenic and likely pathogenic sequence variants in patients who had at least 1 ECG with a QTc ≥500 ms.Methods and ResultsTelemark Hospital Trust is a community hospital within the Norwegian national health system, serving ≈173 000 inhabitants. We searched the ECG database at Telemark Hospital Trust, Norway, from January 2004 to December 2014, and identified 1531 patients with at least 1 ECG with a QTc ≥500 ms. At the time of inclusion in this study (2015), 766 patients were alive. A total of 733 patients were invited to participate, and 475 accepted. The 17 genes that have been reported to cause monogenic LQTS were sequenced among the patients. Pro‐QTc score was calculated for each patient. A molecular genetic cause of LQTS was detected in 31 (6.5%) of 475 patients. These patients had a lower pro‐QTc score than those without pathogenic or likely pathogenic variants (1.7±1.0 versus 2.8±1.6; P<0.001).ConclusionsCompared with the general population, hospitalized patients with a QTc ≥500 ms in at least 1 ECG recording had an increased likelihood for pathogenic and likely pathogenic variants in LQTS genes. We recommend increased awareness of the possibility of LQTS in patients with at least 1 ECG with a QTc ≥500 ms.

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“…It is a typical cardiac repolarization abnormality defined by heart rate-corrected QT interval (QTc) prolongation on resting electrocardiogram (ECG) [4,50], and characterized by an increased trend for ventricular tachycardia with torsade de pointes (TdP). LQTS exists as a congenital genetic disease (cLQTS) with mutations described in different genes, which cause different types of LQTS.…”

Section: Long Qt and Timothy Syndromesmentioning

confidence: 99%

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

et al. 2018

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The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future.

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The genetic basis of long QT and short QT syndromes: A mutation update

Cited by 392 publications

References 424 publications

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

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The genetic basis of long QT and short QT syndromes: A mutation update

Cited by 392 publications

References 424 publications

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP 2 ) sensitivity of I Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP 2 ) sensitivity of I Ks to modulate channel activity

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

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Product

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KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) sensitivity of I _Ks to modulate channel activity