Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome

Neyroud, Nathalie; Denjoy, Isabelle; Donger, Claire; Gary, Françoise; Villain, Elisabeth; Leenhardt, Antoine; Bénali, Karim; Schwartz, Ketty; Coumel, Philippe; Guicheney, Pascale

doi:10.1038/sj.ejhg.5200165

Cited by 39 publications

(16 citation statements)

References 12 publications

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“…Carriers of two mutant alleles had a more pronounced QTc prolongation in JLN1 (32,33,57,63) and in JLN2 (15, 46,49,63). This relationship to QTc prolongation was independent of whether the patient was homozygous for a truncation or a missense mutation.…”

Section: Genotype-phenotype Correlation In Lqt Syndromesmentioning

confidence: 75%

The LQT syndromes – current status of molecular mechanisms

et al. 1999

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Our knowledge on the molecular genetics of inherited cardiac arrhythmias is very recent in comparison to the advances of genetics achieved in other inherited cardiac disorders. This is related to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies that are based on the genetic information obtained from large multi-generation families were made difficult. In 1991, the first chromosomal locus for congenital long-QT (LQT) syndrome was identified on chromosome 11p15.5 (LQT1 locus) by linkage analysis. Meanwhile, the disease-causing gene at the LQT1 locus (KCNQ1), a gene encoding a K+ channel subunit of the IKs channel, and three other, major genes, all encoding cardiac ion channel components, have been identified. Taken together, LQT syndrome turned out to be a heterogeneous channelopathy. Moreover, the power of linkage studies to reveal the genetic causes of the LQT syndrome was also important to identify unknown but fundamental channel components that contribute to the ion currents tuning ventricular repolarization. In-vitro expression of the altered ion channel genes demonstrated in each case that the altered ion channel function produces prolongation of the action potential and thus the increasing propensity to ventricular tachyarrhythmias. Since these ion channels are pharmacological targets of many antiarrhythmic (and other) drugs, individual and potentially deleterious drug responses may be related to genetic variation in ion channel genes. Very recently, also in acquired LQT syndrome, which is a frequent clinical disorder in cardiology a genetic basis has been proposed in part since mutations in LQT genes have been specifically found. The discovery of ion channel defects in LQT syndrome represents the major achievement in our understanding and implies potential therapeutic options. The knowledge of the genomic structure of the LQT genes now offers the possibility to detect the underlying genetic defect in 80-90% of all patients. With this specific information, containing the type of ion channel (Na+ versus K+ channel) and electrophysiological alteration by the mutation (loss-of-function versus change-of-function mutation), gene-directed, elective drug therapies have been initiated in genotyped LQT patients. Based on preliminary data, that were supported by in vitro studies, this approach may be useful in recompensating the characteristic phenotypes in some LQT patients. Mutation detection is a new diagnostic tool which may become of more increasing importance in patients with a normal QTc or just a borderline prolongation of the QTc interval at presentation. These patients represent approximately 40% of all familial cases. Moreover, LQT3 syndrome and idiopathic ventricular fibrillation are allelic disorders and genetically overlap. In both mutations in the LQT3 gene SCN5A encoding the Na+ channel alpha-subunit for INa have been reported. Thus, the clinical nosology of inherited arrhythmias may be reconsidered aft...

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Section: Genotype-phenotype Correlation In Lqt Syndromesmentioning

confidence: 75%

The LQT syndromes – current status of molecular mechanisms

et al. 1999

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“…It is the second missense mutation that causes the JLN syndrome; the first has been identified in the pore. 22 With the 20-bp deletion that we identified in the present study, four of the six known mutations causing the JLN syndrome induced a putative premature truncation of the subunit, 6,11,32 suggesting that frameshift mutations, especially in the C-terminal domain of the KVLQT1 channel, could be responsible for most of the JLN cases. Thus, analysis of the whole KCNQ1 gene will assist in genetic diagnosis of asymptomatic mutation carriers at risk for ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…LQTS mutations have previously been identified in KCNQ1 and reported for some of the families. 6,17,21,22 In the remaining 53 families, clinical evaluation was made and blood samples were collected after written informed consent was obtained in accordance with the guidelines established by the Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale du Groupe Hospitalier de la Pitié-Salpêtrière (Paris, France). All subjects underwent clinical and cardiovascular examinations, including a 12-lead ECG.…”

Section: Subjectsmentioning

confidence: 99%

Genomic Organization of the KCNQ1 K ⁺ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome

Neyroud

Richard

Vignier

et al. 1999

Circulation Research

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102

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Abstract-The voltage-gated Kϩ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K ϩ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the ␣ subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA) n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR-single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1: two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts. (Circ Res. 1999;84:290-297.)

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“…Some mutations identified in the KvLQT1 protein have been associated with milder LQTS phenotypes, with borderline QTc prolongation and a low risk of cardiac arrhythmias in the absence of repolarization prolonging drugs. Mild missense mutations have been described either in the C-terminus region of KvLQT1 [13 -15], or in the pore region [16,17]. In addition, nonsense and frameshift mutations associated with non-penetrant phenotype (no symptoms, QTc normal or borderline) have been identified in heterozygous carriers in JLNS families [7,18 -20].…”

Section: Introductionmentioning

confidence: 99%

New KCNQ1 mutations leading to haploinsufficiency in a general population1Defective trafficking of a KvLQT1 mutant

Gouas

Bellocq

Berthet

et al. 2004

Cardiovascular Research

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Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome

Cited by 39 publications

References 12 publications

The LQT syndromes – current status of molecular mechanisms

The LQT syndromes – current status of molecular mechanisms

Genomic Organization of the KCNQ1 K ⁺ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome

New KCNQ1 mutations leading to haploinsufficiency in a general population1Defective trafficking of a KvLQT1 mutant

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Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome

Cited by 39 publications

References 12 publications

The LQT syndromes – current status of molecular mechanisms

The LQT syndromes – current status of molecular mechanisms

Genomic Organization of the KCNQ1 K + Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome

New KCNQ1 mutations leading to haploinsufficiency in a general population1Defective trafficking of a KvLQT1 mutant

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Genomic Organization of the KCNQ1 K ⁺ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome