Genetical aspects of the cardio‐auditory syndrome of Jervell and Lange‐Nielsen (congenital deafness and electrocardiographic abnormalities)

Fraser, G. R.; Froggatt, P.; Murphy, Thomas Brendan

doi:10.1111/j.1469-1809.1964.tb00469.x

Cited by 116 publications

(63 citation statements)

References 26 publications

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“…Similarly, the JL-N syndrome has not been detected in earlier mentioned study conducted in California [6]. Fraser et al [11] estimated that the incidence of this syndrome in the pediatric population aged 4 to 15 years in England, Wales and Ireland was between 1.6 to 6 in 1,000,000. So far, the highest incidence of JL-N syndrome of at least 1:200,000 has been reported in Norway [12].…”

Section: Discussionmentioning

confidence: 87%

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

Sanecka

Biernacka²,

Szperl³

et al. 2016

Cardiol J.

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Section: Discussionmentioning

confidence: 87%

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

Sanecka

Biernacka²,

Szperl³

et al. 2016

Cardiol J.

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“…The incidence of homozygous mutations in KCNQ1 (also known as Jervell-Lange-Nielsen syndrome) is Ϸ1:500,000, with affected individuals manifesting severe QT prolongation and sensorineural deafness (26). By contrast, viable humans with homozygous KCNH2 mutations are only rarely described in the literature, most likely as a consequence of embryonic lethality.…”

Section: Homozygous Kcnh2 Mutant Embryonic Ventricle Does Not Generatementioning

confidence: 99%

Zebrafish model for human long QT syndrome

Arnaout

Ferrer

Huisken

et al. 2007

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

215

212

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Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K ؉ current (IKr). We show that complete loss of functional IKr in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wildtype function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.cardiac ͉ development ͉ kcnh2 ͉ arrhythmia ͉ electrophysiology A utosomal dominant KCNH2 mutations account for Ϸ45% of mutation-positive long QT syndrome (LQTS) (1, 2). Recessive KCNH2 mutations are rarely reported, implying that most homozygous mutations are embryonic-lethal (3, 4). The cellular mechanisms underlying embryonic lethality are not known. Although LQTS has been extensively characterized in humans, establishing an animal model would be helpful to identify genes that modify phenotypic expressivity or to screen against compounds that cause acquired forms of LQTS. To date, an appropriate animal model of inherited LQTS does not exist. Transgenic strategies and targeted deletion of genes that regulate rapidly activating delayed rectifier K ϩ current (I Kr ) and slow delayed rectifier K ϩ current (I Ks ) in mice fail to produce a significant phenotype (5-7). The mouse heart rate is nearly 10 times faster than that of humans, and thus a distinct cadre of ion channels facilitates ventricular repolarization in mice (5-8).Although the zebrafish heart is two-chambered, its fundamental electrical properties are remarkably similar to those of humans (9). For example, embryonic and adult heart rates are similar to those of humans (10, 11), and the relationship between QT interval and heart rate parallels that of humans (11). Forward-genetic screens using zebrafish have identified many cardiovascular mutants for analysis (12, 13), thereby revealing critical pathways in cardiovascular development that parallel those of higher vertebrates (14). Large clutch size facilitates positional clo...

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“…[2][3][4][5] Two clinical forms of LQTS have been recognised: Romano-Ward syndrome (RWS) with an autosomal dominant pattern of inheritance, 6 and Jervell and Lange-Nielsen syndrome (JLNS) 7 with an autosomal recessive pattern of inheritance and association with sensorineural deafness. However, a relatively high frequency of sudden cardiac death, or clearly prolonged QT c interval among relatives of patients with both RWS 8 and JLNS, 9 and the recent description of recessive RWS associated with homozygosity for a KVLQT1 mutation 10 suggest that the pattern of inheritance may be more complicated.…”

Section: Introductionmentioning

confidence: 99%

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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Genetical aspects of the cardio‐auditory syndrome of Jervell and Lange‐Nielsen (congenital deafness and electrocardiographic abnormalities)

Cited by 116 publications

References 26 publications

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

Zebrafish model for human long QT syndrome

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

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