Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel

Henrion, Ulrike; Zumhagen, Sven; Steinke, Katja; Strutz‐Seebohm, Nathalie; Stallmeyer, Birgit; Läng, Florian; Schulze‐Bahr, Eric; Seebohm, Guiscard

doi:10.1159/000178470

Cited by 55 publications

(51 citation statements)

References 35 publications

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“…The V141M mutation is known to alter the gating of I[Ks] channels, leading to a gain of function and shortening of atrial and ventricular action potentials producing a short QT interval and a propensity for AF and ventricular fibrillation. Interestingly, there have been case reports of patients with overlapping phenotype with long QT syndrome, sinus bradycardia and AF based on loss-of-functional I[Ks] in the ventricles and gain-of-functional I[Ks] in the atria associated with familial AF [12]. Gain-of-function mutation in the KCNQ1 gene has been associated with SQTS [13].…”

Section: Discussionmentioning

confidence: 99%

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Villafañe

Fischbach²,

Gebauer³

2014

Cardiology

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Objectives: Atrial fibrillation (AF) is rare during childhood and usually associated with other cardiovascular pathology. In lone AF, the ventricular response rate is usually rapid. We sought to describe a subset of children who present with early-onset AF and a slow ventricular response rate who were found to have the short QT syndrome (SQTS). Methods: Using a MEDLINE/PubMed search, children with AF, a structurally normal heart and bradycardia were identified. Demographics, clinical presentation, electrocardiographic (ECG) findings, electrophysiologic testing, genetic analysis and follow-up assessment were collected on each child for analysis. Results: Four children were identified in the literature and combined with 2 other children followed by the authors. All had a short QT interval and those who were tested were found to have a gain-of-function mutation in the KCNQ1 gene. Conclusions: We describe a subclass of children with SQTS who present with AF and a slow ventricular response. Medical therapy has not been effective in maintaining sinus rhythm. The long-term outcome remains unknown for these children. This condition may present in utero as persistent bradycardia with postnatal ECG showing a very short QT interval.

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Section: Discussionmentioning

confidence: 99%

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Villafañe

Fischbach²,

Gebauer³

2014

Cardiology

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“…Two-electrode voltage-clamp recordings were performed (55) at a holding potential of Ϫ30 mV for determination of the endogenous Na ϩ /K ϩ -ATPase. The data were filtered at 10 Hz and recorded with a GeneClampex 500 amplifier, a DigiData 1300 A/D-D/A converter, and the pClampfit 9.2 software packages for data acquisition and analysis (Axon Instruments) (38). The control bath solution (superfusate/ND96) contained (in mM): 96 NaCl, 2 KCl, 1.8 CaCl 2, 1 MgCl2, and 5 HEPES, pH 7.4 (NaOH), supplemented with gentamycin (100 mg/l), tetracycline (50 mg/l), and ciprofloxacin (1.6 mg/l).…”

Section: Methodsmentioning

confidence: 99%

Energy-sensitive regulation of Na⁺/K⁺-ATPase by Janus kinase 2

Bhavsar

Hosseinzadeh

Brenner

et al. 2014

American Journal of Physiology-Cell Physiology

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Janus kinase 2 (JAK2) contributes to intracellular signaling of leptin and erythropoietin, hormones protecting cells during energy depletion. The present study explores whether JAK2 is activated by energy depletion and regulates Na+/K+-ATPase, the major energy-consuming pump. In Jurkat cells, JAK2 activity was determined by radioactive kinase assay, phosphorylated JAK2 detected by Western blotting, ATP levels measured by luciferase assay, as well as Na+/K+-ATPase α1-subunit transcript and protein abundance determined by real-time PCR and Western blotting, respectively. Ouabain-sensitive K+-induced currents ( Ipump) were measured by whole cell patch clamp. Ipump was further determined by dual-electrode voltage clamp in Xenopus oocytes injected with cRNA-encoding JAK2, active V617FJAK2, or inactive K882EJAK2. As a result, in Jurkat T cells, JAK2 activity significantly increased following energy depletion by sodium azide (NaN3) or 2,4- dinitro phenol (DNP). DNP- and NaN3-induced decrease of cellular ATP was significantly augmented by JAK2 inhibitor AG490 and blunted by Na+/K+-ATPase inhibitor ouabain. DNP decreased and AG490 enhanced Ipump as well as Na+/K+-ATPase α1-subunit transcript and protein abundance. The α1-subunit transcript levels were also enhanced by signal transducer and activator of transcription-5 inhibitor CAS 285986-31-4. In Xenopus oocytes, Ipump was significantly decreased by expression of JAK2 and V617FJAK2 but not of K882EJAK2, effects again reversed by AG490. In V617FJAK2-expressing Xenopus oocytes, neither DNP nor NaN3 resulted in further decline of Ipump. In Xenopus oocytes, the effect of V617FJAK2 on Ipump was not prevented by inhibition of transcription with actinomycin. In conclusion, JAK2 is a novel energy-sensing kinase that curtails energy consumption by downregulating Na+/K+-ATPase expression and activity.

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“…Xenopus oocytes were prepared as previously described [37,38]. Where not indicated otherwise, 10 ng PEPT1 and PEPT2 cRNA were injected on the first day and 10 ng of wild type JAK2 cRNA injected on the second day or same day after preparation of the oocytes [39].…”

Section: Methodsmentioning

confidence: 99%

Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

Hosseinzadeh

Luo

Bhavsar

et al. 2013

Cell Physiol Biochem

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Background/Aims: Janus-activated kinase-2 JAK2 participates in the signaling of several hormones including growth hormone, fosters tumor growth and modifies the activity of several Na⁺ coupled nutrient transporters. Peptide uptake into intestinal and tumor cells is accomplished by electrogenic peptide transporters PEPT1 and PEPT2. The present study thus explored whether JAK2 contributes to the regulation of PEPT1 and PEPT2 activity. Methods: cRNA encoding either PEPT1 or PEPT2 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, constitutively active ^V617FJAK2 or inactive ^K882EJAK2. The current created by the dipeptide glycine-glycine (I_gly-gly) was determined by dual electrode voltage clamp and taken as measure for electrogenic peptide transport. Results: No appreciable I_gly-gly was observed in water injected oocytes. In PEPT1 or PEPT2 expressing oocytes I_gly-gly was significantly increased by additional coexpression of JAK2. As shown in PEPT1 expressing oocytes, I_gly-gly without significantly modifying the concentration required for halfmaximal I_gly-gly (K_M). Following disruption of carrier insertion with brefeldin A (5 µM) I_gly-gly declined similarly fast in Xenopus oocytes expressing PEPT1 with JAK2 and in Xenopus oocytes expressing PEPT1 alone. In oocytes expressing both, PEPT1 and ^V617FJAK2, I_gly-gly was gradually decreased by JAK2 inhibitor AG490 (40 µM). According to Ussing chamber experiments pharmacological JAK2 inhibition similarly decreased I_gly-gly in mouse intestine. Conclusion: Regulation of the peptide transporters PEPT and PEPT2 does involve the Janus-activated kinase-2 JAK2.

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Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel

Cited by 55 publications

References 35 publications

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Energy-sensitive regulation of Na⁺/K⁺-ATPase by Janus kinase 2

Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

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Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel

Cited by 55 publications

References 35 publications

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia

Energy-sensitive regulation of Na+/K+-ATPase by Janus kinase 2

Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

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Product

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Energy-sensitive regulation of Na⁺/K⁺-ATPase by Janus kinase 2