Original-experimental geneticFunctional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome
Introduction
Long QT syndrome (LQTS) is a cardiac disease characterized by prolongation of the QT interval on ECG. Patients suffer from syncopal episodes due to ventricular arrhythmias such as torsades de pointes and are at risk for sudden death.1 LQTS is genetically heterogeneous. It is caused by mutations in genes coding for cardiac ion channel subunits involved in the cardiac action potential, that is, KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), KCNE2 (LQT6), and SCN5A (LQT3).2 KCNQ1 and KCNH2 code for α-subunits of voltage-gated potassium channels (KCNQ1 [Kv7.1] and HERG1 [Kv11.1], respectively), and SCN5A encodes a sodium channel α-subunit. KCNE1 and KCNE2 code for β-subunits also termed minK and MiRP1. KCNE1 and KCNE2 combine with KCNQ1 and HERG1 to constitute the repolarizing potassium currents in the cardiac action potential, IKs and IKr.3, 4 Mutations in ANK2 (LQT4), coding for the membrane receptor ankyrin B, and mutations in the genes KCNJ2 and CACNA1C, coding for the ion channel α-subunits involved in IKl and ICaL, can cause LQTS.5, 6, 7 Although LQTS is known to cause severe cardiac arrhythmias, not all mutation carriers have symptoms, and only a few die of cardiac events.8 It has been postulated that a large proportion of LQTS carriers appear unaffected due to low penetrance.9 Further diversity appears to arise from an increasing number of reports of compound heterozygosity within one or even two different LQTS genes.10, 11, 12, 13 Schwartz et al14 suggested that compound mutations increase the risk of arrhythmia. Westenskow et al12 demonstrated that LQTS-associated compound mutations may cause a more severe phenotype and are common. Only one study to date has reported mutations in both KCNQ1 and KCNH2, including functional analyses.13
In this report, we used cascade screening and functional studies to evaluate the contributions from the concomitant KCNQ1 (R591H) and HERG1 (R328C) mutations in a family with LQTS. Whereas the mutation in KCNQ1 led to a dramatic reduction in current and was sufficient to explain the phenotype, the HERG1 mutation appeared to have no impact. Mimicking the compound state in the patient by coexpression experiments demonstrated that the reduction in the current density was equivalent to the effect of the KCNQ1 mutation alone.
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Patients
Among patients referred to Statens Serum Institut from St. George’s Hospital, London, United Kingdom, for molecular/genetic workup for LQTS, a British family with mutations in both KCNH2 and KCNQ1 was selected for careful clinical and electrophysiologic assessment. Subjects gave informed consent. The clinical evaluation included history, family history, examination, 12-lead ECG, and exercise and ambulatory ECG monitoring whenever possible. The QT interval was corrected using Bazett’s formula,
Phenotypic characterization
The pedigree of the family is shown in Figure 1. The proband (18.1) presented at age 58 years with multiple syncopal episodes and a single episode of aborted cardiac arrest due to ventricular tachycardia. She was diagnosed with LQTS and treated with β-adrenergic blockers and an implantable cardioverter-defibrillator (ICD). The proband had four children. The youngest child was a boy with a diagnosis of status epilepticus who died suddenly at age 12 years. DNA material from the dead boy was
Discussion
In this study, the sequences of all exons of the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in a British family with LQTS were analyzed. The proband was heterozygous for missense mutations in two individual genes, namely, R591H in KCNQ1 and R328C in KCNH2. The KCNQ1 mutation has been described.17 The mutation in KCNH2 was considered novel but now has been described as LQTS associated.18 Neither had been functionally characterized. The KCNH2 mutation had been identified in only two unrelated
Conclusion
Molecular screening of all family members of genotyped patients to minimize the risk of sudden death in mutation carriers is appropriate. Nevertheless, analysis of the functional effects of any mutant in order to fully understand the pathogenetic impact and severity of the disease is crucial. Only then can appropriate clinical management proceed.
Acknowledgments
We thank Birthe Lynderup, Jette Rasmussen, and Mette Hougaard for excellent technical assistance.
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2015, Canadian Journal of CardiologyA590T mutation in KCNQ1 C-terminal helix D decreases I<inf>Ks</inf> channel trafficking and function but not Yotiao interaction
2014, Journal of Molecular and Cellular CardiologyCitation Excerpt :The previously reported mutations in the vicinity of A590 also exerted similar effects on IKs amplitude and membrane trafficking. As compared with the reported mutations, the A590T mutation caused mild reduction in IKs amplitude (Fig. 2A, B) and cell surface expression (Fig. 3) [23–26,29,31]. This suggests that the severity of IKs function impairment reflects the severity of the decreased cell surface expression level.
Characterization of a novel mutant KCNQ1 channel subunit lacking a large part of the C-terminal domain
2013, Biochemical and Biophysical Research Communications
This work was supported by The John and Birthe Meyer Foundation, The Velux Foundation, The NovoNordisk Foundation, The Danish Heart Foundation, and The Beckett Foundation.
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The first two authors share first authorship.