Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

Tristani‐Firouzi, Martin; Jensen, Judy L; Donaldson, Matthew R.; Sansone, Valeria; Meola, Giovanni; Hahn, Angelika F.; Bendahhou, Saı̈d; Kwieciński, Hubert; Fidziańska, Anna; Plaster, Nikki; Fu, Ying‐Hui; Ptáček, Louis J.; Tawil, Rabi

doi:10.1172/jci200215183

Cited by 147 publications

(241 citation statements)

References 32 publications

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“…These observations were considered to be the global phenomena corresponding to the abbreviated APs and long QT-phenotype APs observed in the overexpressed and suppressed myocytes, respectively. The QTc prolongation seen in Kir2.1-suppressed animals supports the clinical observations made with Andersen syndrome (3,4). This is especially relevant since conditions that favor AP prolongation are also prerequisite for the development of early afterdepolarizations (27), which are presumptive triggers for ventricular arrhythmias (28).…”

supporting

confidence: 66%

Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

Miake¹,

Marbán²,

Nuss³

2003

J. Clin. Invest.

179

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The inward rectifier current IK1 is tightly regulated regionally within the heart, downregulated in heart failure, and genetically suppressed in Andersen syndrome. We used in vivo viral gene transfer to dissect the role of IK1 in cardiac repolarization and maintenance of the resting membrane potential (RMP) in guinea pig ventricular myocytes. Kir2.1 overexpression boosted Ba2+-sensitive IK1 by more than 100% (at –50mV), significantly shortened action potential durations (APDs), accelerated phase 3 repolarization, and hyperpolarized RMP compared with control cells (nongreen cells from the same hearts and green cells from GFP-transduced hearts). The dominant-negative Kir2.1AAA reduced IK1 by 50–90%; those cells with less than 80% reduction of IK1 exhibited prolonged APDs, decelerated phase 3 repolarization, and depolarization of the RMP. Further reduction of IK1 resulted in a pacemaker phenotype, as previously described. ECGs revealed a 7.7% ± 0.9% shortening of the heart rate–corrected QT interval (QTc interval) in Kir2.1-transduced animals (n = 4) and a 16.7% ± 1.8% prolongation of the QTc interval (n = 3) in Kir2.1AAA-transduced animals 72 hours after gene delivery compared with immediate postoperative recordings. Thus, IK1 is essential for establishing the distinctive electrical phenotype of the ventricular myocyte: rapid terminal repolarization to a stable and polarized resting potential. Additionally, the long-QT phenotype seen in Andersen syndrome is a direct consequence of dominant-negative suppression of Kir2 channel function

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supporting

confidence: 66%

Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

Miake¹,

Marbán²,

Nuss³

2003

J. Clin. Invest.

179

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“…Clinical phenotypes of patients with ATS include periodic paralysis, developmental dysmorphisms, and prolonged QT intervals. Mutations in KCNJ2 were found to underlie this multisystem disorder (55)(56)(57). KCNJ2 encodes the inward rectifier K + channel α subunit Kir2.1, which is expressed in skeletal and cardiac muscle.…”

Section: Lqts Variants and Multisystem Disordersmentioning

confidence: 99%

Long QT syndrome: from channels to cardiac arrhythmias

Moss

Kass²

2005

Journal of Clinical Investigation

259

187

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Long QT syndrome, a rare genetic disorder associated with life-threatening arrhythmias, has provided a wealth of information about fundamental mechanisms underlying human cardiac electrophysiology that has come about because of truly collaborative interactions between clinical and basic scientists. Our understanding of the mechanisms that control the critical plateau and repolarization phases of the human ventricular action potential has been raised to new levels through these studies, which have clarified the manner in which both potassium and sodium channels regulate this critical period of electrical activity.

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“…Both syndromes are caused predominantly by mutations of genes that encode for cardiac ion channels. At present, over 200 mutations in five potassium channel genes (KCNQ1, HERG, KCNE1, KCNE2, KCNJ2) [10][11][12][13][14], one sodium channel gene (SCN5A) [15], and one non-ion channel protein (Ankyrin-B) [16] that is involved in the structural integrity of ion channels have been identified. Recently, mutations in the L-type calcium channel (CaV1.2) gene were found to be responsible for QT prolongation in Timothy syndrome, a multisystem disorder that causes syncope and sudden death [17].…”

Section: The Long-qt Syndromementioning

confidence: 99%

Cardiac arrhythmias and sudden death in infancy: implication for the medicolegal investigation

et al. 2006

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Genetically transmitted diseases are an important cause of juvenile sudden cardiac death (SCD). In a considerable proportion of individuals in which a medicolegal investigation is performed, structural heart disease is absent, and the medical examiner fails to discover an adequate cause of death. In such cases, an inherited arrhythmogenic disease should be considered, which manifests with life-threatening ventricular tachycardia or SCD. Molecular diagnosis is progressively becoming an important tool for these questions. Therefore, postmortem genetic testing ("molecular autopsy") should be considered as a part of the comprehensive medicolegal investigation in SCD cases without apparent structural heart disease. It will have implications not only for the deceased individual but also for living family members in preventing (further) cardiac events by expert counseling, appropriate lifestyle adjustment, and adequate treatment, if available.

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Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

Cited by 147 publications

References 32 publications

Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

Long QT syndrome: from channels to cardiac arrhythmias

Cardiac arrhythmias and sudden death in infancy: implication for the medicolegal investigation

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