Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome

Millat, Gilles; Chevalier, Philippe; Restier-Miron, Lioara; Costa, Antoine Da; Bouvagnet, Patrice; Kugener, Béatrice; Fayol, L; Armengod, C. González; Oddou, B; Chanavat, Valérie; Froidefond, E; Perraudin, R; Rousson, Robert; Rodriguez-Lafrasse, Claire

doi:10.1111/j.1399-0004.2006.00671.x

Cited by 83 publications

(55 citation statements)

References 76 publications

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“…Inherited loss-of-function mutations of Kv7.1 and KCNE1 are associated with long QT syndrome (LQT), in which the ventricular action potential duration is prolonged, resulting in a high risk of ventricular arrhythmias and sudden death. Eleven previously reported LQT-associated mutations (39)(40)(41)(42)(43)(44)(45)(46) affect basic residues in the PIP 2 pocket (Table S1). For these mutations, loss of VSD-PD coupling may compromise the I Ks channel function and create a substrate for cardiac arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Zaydman

Silva

Delaloye

et al. 2013

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

184

313

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Voltage-gated ion channels generate dynamic ionic currents that are vital to the physiological functions of many tissues. These proteins contain separate voltage-sensing domains, which detect changes in transmembrane voltage, and pore domains, which conduct ions. Coupling of voltage sensing and pore opening is critical to the channel function and has been modeled as a protein-protein interaction between the two domains. Here, we show that coupling in Kv7.1 channels requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We found that voltage-sensing domain activation failed to open the pore in the absence of PIP 2 . This result is due to loss of coupling because PIP 2 was also required for pore opening to affect voltage-sensing domain activation. We identified a critical site for PIP 2 -dependent coupling at the interface between the voltage-sensing domain and the pore domain. This site is actually a conserved lipid-binding site among different K + channels, suggesting that lipids play an important role in coupling in many ion channels.V oltage-gated ion channels are integral membrane proteins that sense membrane voltage and respond by opening or closing a transmembrane pore. Ionic currents carried by voltage-gated ion channels control contraction in muscle, encode information in the nervous system, and trigger secretion in neurohormonal tissues. Voltage-gated ion channels contain four voltage-sensing domains (VSDs) and a central pore domain (PD) that are structurally distinct (1, 2). In voltage-gated potassium (Kv) channels, the first four transmembrane segments (S1-S4) of each α-subunit forms a VSD. In response to changes in transmembrane voltage, the VSD undergoes a conformational change, called activation, during which membrane depolarization moves the S4 segment outward (3). The PD is formed by the last two transmembrane segments (S5, S6) from four α-subunits and undergoes a mainly voltageindependent conformational change during which the intracellular ends of the S6 segments bend, opening the ionic pore (4, 5). Interestingly, the PD and VSD can exist in pore-only (6) and voltage sensor-only proteins, respectively, where they function independently (7,8). Confining sensitivity to voltage, or to other stimuli, within a domain diversifies the ion channel properties that can be achieved by partnering different pore and sensor domains. However, this modular architecture also raises a fundamental question as to how VSD activation is transmitted to the PD. Previous studies of this coupling process have revealed the importance of direct protein-protein interactions at the VSD-PD interface (9-13); however, the possible role of membrane lipids in VSD-PD coupling remains undetermined.The membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) modulates the activity of many ion channels, including some voltage-gated channels (14). Notably, all members of the Kv7 family (Kv7.1-Kv7.5), which play important physiological roles in the cardiac (15) or the nervous (16) systems, require PIP 2 to be opened by...

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Section: Discussionmentioning

confidence: 99%

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Zaydman

Silva

Delaloye

et al. 2013

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

184

313

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“…The nsSNPs scores found to have functional significance by both SIFT and PolyPhen are shown bold in Tables 2 and 3. The results obtained by these programs partially concur with the experimental works reported earlier. Notably, the SNP with an id rs179489 in KCNQ1 (Splawski et al 1998), rs36210422 (Laitinen et al 2000) and rs41313074 (Splawski et al 2000) in KCNH2, rs28937316 (Splawski et al 2000), rs6791924 (Yang et al 2002) and rs28937318 (Smits et al 2002) in SCN5A, rs28933384 (Schulze-Bahr et al 1997 in KCNE1, and rs2234916 (Millat et al 2006), rs16991654 (Millat et al 2006) and rs35759083 (Millat et al 2006) in KCNE2 gene reported through experimental work were also predicted to be the deleterious mutations by the SIFT and PolyPhen programs. There are a few other mutations, which are depicted as 'Predicted in this work' in Tables 2 and 3, that have not been reported experimentally so far, but must be worked out in the future.…”

Section: Damaged Nssnp Found By the Polyphen Algorithmmentioning

confidence: 99%

In silico investigations on functional and haplotype tag SNPs associated with congenital long QT syndromes (LQTSs)

Sudandiradoss

Sethumadhavan

2008

HUGO J

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Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. It is still a major challenge to identify the functional SNPs in disease-related genes. In this review, the genetic variation that can alter the expression and the function of the genes, namely KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2, with the potential role for the development of congenital long QT syndrome (LQTS) was analyzed. Of the total of 3,309 SNPs in all five genes, 27 non-synonymous SNPs (nsSNPs) in the coding region and 44 SNPs in the 5 0 and 3 0 un-translated regions (UTR) were identified as functionally significant. SIFT and PolyPhen programs were used to analyze the nsSNPs and FastSNP; UTR scan programs were used to compute SNPs in the 5 0 and 3 0 untranslated regions. Of the five selected genes, KCNQ1 has the highest number of 26 haplotype blocks and 6 tag SNPs with a complete linkage disequilibrium value. The gene SCN5A has ten haplotype blocks and four tag SNPs. Both KCNE1 and KCNE2 genes have only one haplotype block and four tag SNPs. Four haplotype blocks and two tag SNPs were obtained for KCNH2 gene. Also, this review reports the copy number variations (CNVs), expressed sequence tags (ESTs) and genome survey sequences (GSS) of the selected genes. These computational methods are in good agreement with experimental works reported earlier concerning LQTS.

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“…Examples of such methods are direct sequencing, denaturing high performance liquid chromatography (DHPLC), single strand conformational polymorphism analysis (SSCP), HRM analysis, and next-generation sequencing (NGS). 3,[8][9][10][11][12] Some methods for large-scale detection of the 3 major LQTScausing gene mutations are expensive and technically timeconsuming. Since 2002, HRM analysis has represented the next generation of mutation scanning technology and offers considerable time and cost savings over those methods.…”

Section: Ong Qt Syndrome (Lqts) Is a Congenital Arrhyth-mentioning

confidence: 99%

Mutation Analysis of KCNQ1, KCNH2 and SCN5A Genes in Taiwanese Long QT Syndrome Patients

et al. 2015

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SummaryLong QT syndrome (LQTS) is a genetic cardiac disease. Gene mutation affects the structure or function of ion channels that are associated with a high risk of sudden death. The goal of this study was to determine the frequency of KCNQ1, KCNH2, and SCN5A mutations in LQTS in a Taiwanese population. Genomic DNA was extracted from peripheral blood samples obtained from 5 patients with LQTS and the family members of 3 LQTS patients. High resolution melting (HRM) analysis and direct DNA sequencing were used to characterize the KCNQ1, KCNH2, and SCN5A genetic variations. HRM analysis was successfully optimized for 14 of the 16 exons of the KCNQ1, 5 of the 15 exons of the KCNH2, and 23 of the 27 exons of the SCN5A. HRM and direct DNA sequencing was applied to the cohort of 5 cases and some of their family. The genetic testing revealed two pathogenic mutations (p.T309I in KCNQ1 and p.R744fs in KCNH2) and all of the mutational frequencies in KCNQ1 and KCNH2 were 20%. In the two patients who carry the pathogenic mutation presenting with recurrent syncope due to ventricular fibrillation, an implantable cardioverter defibrillator was implanted. We also discovered 11 polymorphisms in KCNQ1, 3 in KCNH2, and 5 in SCN5A. Two-fifths of cases (40%) presented with one of the three major LQTS-causing gene mutations. (Int Heart J 2015; 56: 450-453)

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Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome

Cited by 83 publications

References 76 publications

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening

In silico investigations on functional and haplotype tag SNPs associated with congenital long QT syndromes (LQTSs)

Mutation Analysis of KCNQ1, KCNH2 and SCN5A Genes in Taiwanese Long QT Syndrome Patients

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