Genomic Structure of Three Long QT Syndrome Genes:KVLQT1, HERG,andKCNE1

doi:10.1006/geno.1998.5361

Genomics

Volume 51, Issue 1, 1 July 1998, Pages 86-97

https://doi.org/10.1006/geno.1998.5361 Get rights and content

Abstract

Long QT syndrome (LQT) is a cardiac disorder causing syncope and sudden death from arrhythmias. LQT is characterized by prolongation of the QT interval on electrocardiogram, an indicationof abnormal cardiac repolarization. Mutations inKVLQT1, HERG, SCN5A,andKCNE1,genes encoding cardiac ion channels, cause LQT. Here, we define thecomplete genomic structure of three LQT genesand use this information to identify disease-associated mutations.KVLQT1is composed of 16 exonsand encompasses approximately 400 kb.HERGconsists of 16 exons and spans 55 kb. Three exons make upKCNE1.Each intron of these genes contains the invariant GT and AG at the donor and acceptor splice sites, respectively. Intron sequences were used to design primer pairs for the amplification of all exons. Familial and sporadic cases affected bymutations inKVLQT1, HERG,andKCNE1can nowbe genetically screened to identify individuals at risk of developing this disorder. This work has clinical implications for presymptomatic diagnosis and therapy.

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Cited by (222)

Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity
2017, Heart Rhythm
Congenital long QT syndrome (LQTS) is an inherited, potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70%, with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity.
To describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population.
Fifty-six Saudi families with LQTS were consecutively recruited and evaluated. Sequencing of KCNQ1, KCNH2, and SCN5A genes was conducted on all probands, followed by screening of family relatives.
Genetic analysis was positive in 32 (57.2%) families, with mutations in KCNQ1 identified in 28 families (50%). Surprisingly, 17 (53.1%) probands were segregating homozygous mutations. Family screening identified 123 individuals with mutations; 89 (72.4%) were heterozygous, 23 (18.7%) were homozygous, and 11 (8.9%) were compound heterozygous. Compared to heterozygous, the phenotype was more severe in homozygous individuals, with cardiac symptoms in 78.3% (vs 12.4%), family history of sudden death in 64.7% (vs 44.4%), and prolonged QT interval in 100% (vs 43.8%). Congenital deafness was found in 11 (47.8%) homozygous probands.
Our study provides insight into the clinical and molecular profiles of LQTS in a consanguineous population. It underscores the importance of preemptive management in homozygous patients with LQTS and the value of clinical and molecular screening of at-risk relatives.
Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome
2015, International Journal of Cardiology
Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated.
We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+ 14 mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3–6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35 ± 19 years, n = 30; SQT2: 17 ± 25 years, n = 8, SQT3–6: 19 ± 15 years, n = 15; p = 0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p < 0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p = 0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized.
We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.
A novel KCNQ1 splicing mutation in patients with forme fruste LQT1 aggravated by hypokalemia
2014, Journal of Cardiology
Several KCNQ1 splicing mutations have been identified in patients with type-1 long QT syndrome (LQT1). It was suggested that the clinical severity may differ according to the aberrant splicing products. There may be precipitating factors that cause cardiac events in those with a mild clinical phenotype (forme fruste LQT1).
We analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 31 consecutive LQTS patients. A novel KCNQ1 1251+1G>A (IVS9+1G>A) mutation was identified in three probands and their two relatives. The QT interval in all of the five individuals with mutation was not much prolonged in the absence of precipitating factors (mean QTc was 461 ± 30 ms.). Two of the five individuals with mutation were symptomatic. One patient (a 38-year-old female) had experienced recurrent episodes of syncope due to ventricular tachyarrhythmias (VTAs) accompanied by QT prolongation (QTc: 750 ms) when the serum potassium concentration ([K⁺]) was 2.7 mEq/L. After correction of [K⁺], the QTc interval was shortened to 515 ms, and the occurrence of VTAs ceased. Another patient (a 22-year-old female) was resuscitated from cardio-pulmonary arrest due to VTAs. Just after resuscitation, the QTc interval was 629 ms, and [K⁺] was 2.9 mEq/L. After correction of [K⁺], the QTc interval was dramatically shortened to 440 ms. In order to identify abnormal splicing products of the responsible mutation, we analyzed the reverse transcription-polymerase chain reaction products from peripheral bloods of the mutation carrier, and identified exon 9-skipping (Δ9) and cryptic sequential exons 8 and 9-skipping (Δ8–9) products, as well as a no exon-skipping product.
We identified a novel KCNQ splicing mutation 1251+1G>A in forme fruste LQT1, which induces cryptic splicing. Two of the five individuals with mutation experienced VTAs in the setting of hypokalemia, emphasizing the need to increase awareness of the significance of hypokalemia in this subgroup of LQT1 patients.
Dysfunctional potassium channel subunit interaction as a novel mechanism of long QT syndrome
2013, Heart Rhythm
The slowly-activating delayed rectifier current I_Ks contributes to repolarization of the cardiac action potential, and is composed of a pore-forming α-subunit, KCNQ1, and a modulatory β-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 exerts its extensive control over the kinetics of I_Ks remains unresolved
To evaluate the impact of a novel KCNQ1 mutation on I_Ks channel gating and kinetics
KCNQ1 mutations were expressed in Xenopus oocytes in the presence and absence of KCNE1. Voltage clamping and MODELLER software were used to characterize and model channel function. Mutant and wt genes were cloned into FLAG, Myc and HA expression vectors to achieve differential epitope tagging, and expressed in HEK293 cells for immunohistochemical localization and surface biotinylation assay.
We identified 2 adjacent mutations, S338F and F339S, in the KCNQ1 S6 domain in unrelated probands. The novel KCNQ1 S338F mutation segregated with prolonged QT interval and torsade de pointes; the second variant, F339S, was associated with fetal bradycardia and prolonged QT interval, but no other clinical events. S338F channels expressed in Xenopus oocytes had slightly increased peak conductance relative to wild type, with a more positive activation voltage. F339S channels conducted minimal current. Unexpectedly, S338F currents were abolished by co-expression with intact WT KCNE1 or its C-terminus (aa63-129), despite normal membrane trafficking and surface co-localization of KCNQ1 S338F and wt KCNE1. Structural modeling indicated that the S338F mutation specifically alters the interaction between the S6 domain of one KCNQ1 subunit and the S4-S5 linker of another, inhibiting voltage-induced movement synergistically with KCNE1 binding.
A novel KCNQ1 mutation specifically impaired channel function in the presence of KCNE1. Our structural model shows that this mutation effectively immobilizes voltage gating by an inhibitory interaction that is additive with that of KCNE1. Our findings illuminate a previously unreported mechanism for LQTS, and validate recent theoretical models of the closed state of the KCNQ1:KCNE1 complex.
Concealed Long-QT Syndrome with Rare KCNQ1 Gene Mutation in an Elderly Female: A Case Report
2024, Heart Surgery Forum
Identification and characterization of two novel KCNH2 mutations contributing to long QT syndrome
2024, PLoS ONE

View all citing articles on Scopus

¹: To whom correspondence should be addressed at Eccles Institute of Human Genetics, 15 N 2030 E Room 6110B, University of Utah, Salt Lake City, UT 84112. Telephone: (801) 581-8904. Fax: (801) 585-7423. E-mail:[email protected].

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Regular ArticleGenomic Structure of Three Long QT Syndrome Genes:KVLQT1, HERG,andKCNE1

Abstract

Cell

Am. Heart J.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Cell

Neuron

Cell

KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current

Nature

Molecular mechanism for an inherited cardiac arrhythmia

Nature

Properties of KvLQT1 K+

EMBO J.

KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome

Circulation

Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome

Circulation

Multiple mechanisms of sodium channel-linked long QT syndrome

Circ. Res.

Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel

Proc. Natl. Acad. Sci. USA

Two long QT syndrome loci map to chromosome 3 and 7 with evidence for further heterogeneity

Nat. Genet.

Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel

Circulation

Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harveyras

Science

Consistent linkage of the long QT syndrome to the Harveyras

Am. J. Hum. Genet.

Electrophysiological characterization of an alternatively processed ERG K+

Circ. Res.

Regular Article
Genomic Structure of Three Long QT Syndrome Genes:KVLQT1, HERG,andKCNE1

Properties of KvLQT1 K⁺

Electrophysiological characterization of an alternatively processed ERG K⁺