<i>KVLQT1</i>
            C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome

Donger, Claire; Denjoy, Isabelle; Berthet, Myriam; Neyroud, Nathalie; Cruaud, Corinne; Bennaceur, M.; Chivoret, G; Schwartz, Ketty; Coumel, Philippe; Guicheney, Pascale

doi:10.1161/01.cir.96.9.2778

Cited by 316 publications

(175 citation statements)

References 19 publications

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“…However, LQTS symptoms had appeared in some members of the French family upon administration of drugs prolonging ventricular repolarisation. 16 The findings of recessive RWS caused by compound heterozygosity, as in our family, and by homozygosity in a consanguinous family 10 imply that the frequency of gene carriers is much higher than inferred from the rarity of RWS if the pattern of inheritance was strictly dominant. Therefore 'sporadic RWS' should be considered as potentially recessive RWS, and efforts should be made to determine the molecular defects and identify carriers in the family, since they may be at risk of dying suddenly from drug-induced LQTS.…”

Section: Discussionmentioning

confidence: 47%

“…This is the third description of a RWS family with mutations in the region of the KVLQT1 gene encoding the C-terminal part of the channel subunit, outside the important transmembrane segments. 16,17 In a French family 16 and the family described here, the heterozygotes displayed minor or no QT-prolongation, indicating that C-terminal mutations may have a relatively mild effect on the potassium channel function. However, LQTS symptoms had appeared in some members of the French family upon administration of drugs prolonging ventricular repolarisation.…”

Section: Discussionmentioning

confidence: 63%

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Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene

et al. 1999

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We describe a Swedish family with the proband and his brother suffering from severe RomanoWard syndome (RWS) associated with compound heterozygosity for two mutations in the KVLQT1 (also known as KCNQ1 and KCNA9) gene (R518X and A525T). The mutations were found to segregate as heterozygotes in the maternal and the paternal lineage, respectively. None of the heterozygotes exhibited clinical long QT syndrome (LQTS). No hearing defects were found in the proband. The data strongly indicates that the compound heterozygosity for R518X and A525T is the cause of an autosomal recessive form of RWS in this family. Our findings support the implication of a higher frequency of gene carriers than previously expected. We suggest that relatives of 'sporadic RWS' patients should be considered potential carriers, at risk of dying suddenly from drug-induced LQTS.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 63%

Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene

et al. 1999

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“…Indeed, several mutations in this region of KvLQT1 have been found in RW patients with severe clinical presentation, such as exercise-induced syncopes, sudden death and major QTc prolongation. 7,10,11 As shown in Table 1, the mean QTc value of RW patients was higher than 470 ms. In contrast, only two of the seven heterozygous JLN carriers (two females) displayed a QTc value higher than 440 ms and none of them were symptomatic.…”

Section: Discussionmentioning

confidence: 82%

“…d We had no information concerning the symptoms of the three RW patients in the Russell et al study 10 . Moreover, the 30 RW patients of this table do not include 7 individuals who died suddenly without knowledge of their ECG 11 . Additional RW mutations have been reported in the pore of KvLQT1 without knowledge of the corresponding QTc values: G306R, T312I and I313M 7,14 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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Mutations in KvLQT1, a gene encoding a potassium channel, cause both the recessive Jervell and Lange-Nielsen (JLN) syndrome and the dominant Romano-Ward (RW) syndrome. These diseases are characterised by a prolonged QT interval on the ECG, syncopes and sudden death due to cardiac arrhythmias. The JLN syndrome is also associated with a congenital bilateral deafness. We report here a novel missense mutation, W305S, in the pore region of KvLQT1 identified by PCR-SSCP analysis in two consanguineous JLN families. In contrast to several missense mutations found in the same region of KvLQT1 in RW patients which are associated with severe cardiac phenotypes, the W305S mutation is responsible for an apparently normal phenotype in heterozygous JLN carriers.

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“…The QT interval measured before drug exposure tends to be longer in patients who later develop drug-induced LQTS than in individuals who receive the same agent safely (11, 12). Moreover, sporadic mutations have been identified in patients with drug-induced TdP (9,13,14). Thus, we demonstrated previously that patients with ''acquired'' LQTS can have a genetic predisposition to arrhythmia because of mutation in the MinK-related peptide 1 (MiRP1) subunit of their I Kr potassium channels (9).…”

mentioning

confidence: 99%

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Sesti

Abbott

Wei

et al. 2000

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

436

281

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Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel IKr that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in Ϸ1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.MiRP1 ͉ LQTS ͉ SNP ͉ Bactrim ͉ sulfamethoxazole I nherited long QT syndrome (LQTS) is an uncommon cardiac arrhythmia that predisposes to torsades de pointes (TdP), ventricular fibrillation, and sudden death (1-4). The molecular basis for LQTS is known: delayed repolarization of the myocardium prolongs the cardiac action potential increasing the QT interval measured on the surface electrocardiogram. Mutations in five ion channel genes cause the majority of cases of inherited LQTS. LQTS mutations in SCN5A increase activity of the sodium channel that depolarizes the myocardium to initiate the cardiac action potential (5); LQTS mutations in KCNE1 or KvLQT1 (encoding subunits of I Ks channels) and KCNE2 or HERG (encoding subunits of I Kr channels) diminish potassium fluxes that repolarize the heart to end each beat (6-9).Acquired LQTS is a common disorder caused by drugs and metabolic abnormalities. The risk for acquired LQTS increases when factors that decrease potassium flux act concurrently to impair the ability of the myocardium to repolarize. Wellrecognized conditions that diminish ''repolarization reserve'' include female gender, hypokalemia, and drugs that inhibit cardiac potassium channels (10). Several lines of evidence suggest that patients with drug-induced LQTS have an underlying predisposition to dysrrhythmia. The QT interval measured before drug exposure tends to be longer in patients who later develop drug-induced LQTS than in individuals who receive the same agent safely (11, 12). Moreover, sporadic mutations have been identified in patients with drug-induced TdP (9,13,14). Thus, we demonstrated previously that patients with ''acquired'' LQTS can have a genetic predisposition to arrhythmia because of mutation in the MinK-related peptide 1 (MiRP1) subunit of their I Kr potassium channels (9). In that study, a woman with clarithromycin-induced TdP was found to carry a sporadic missense mutation in KCNE2; channels formed with the altered subunit (Q9E-MiRP1) were abnormal at bas...

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KVLQT1 C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome

Abstract: Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.

Cited by 316 publications

References 19 publications

Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene

Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene

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

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

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