Retention in the Endoplasmic Reticulum as a Mechanism of Dominant-negative Current Suppression in Human Long QT Syndrome

2000 ◽  
Vol 32 (12) ◽  
pp. 2327-2337 ◽  
Author(s):  
Eckhard Ficker ◽  
Adrienne T Dennis ◽  
Carlos A Obejero-Paz ◽  
Pasqualina Castaldo ◽  
Maurizio Taglialatela ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Long Qt Syndrome ◽  
Dominant Negative ◽  
Long Qt ◽  
Negative Current ◽  
Qt Syndrome

scholarly journals The Trafficking of Mutant HERG K+ Channels Linked to Long QT Syndrome are Regulated by a Subdomain in the Endoplasmic Reticulum

2011 ◽  
Vol 100 (3) ◽  
pp. 427a
Author(s):  
Jennifer L. Smith ◽  
Parvathi Nataraj ◽  
Craig T. January ◽  
Brian P. Delisle
Keyword(s):  
Endoplasmic Reticulum ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
K Channels ◽  
Qt Syndrome

scholarly journals Trafficking Deficient KV11.1 (HERG) Mutations Linked to Long QT Syndrome Localize to Different Endoplasmic Reticulum Subcompartments

2016 ◽  
Vol 110 (3) ◽  
pp. 105a
Author(s):  
Jennifer L. Smith ◽  
Corey L. Anderson ◽  
Criag T. January ◽  
Brian Delisle
Keyword(s):  
Endoplasmic Reticulum ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Early somatic mosaicism is a rare cause of long-QT syndrome

2016 ◽  
Vol 113 (41) ◽  
pp. 11555-11560 ◽  
Author(s):  
James Rush Priest ◽  
Charles Gawad ◽  
Kristopher M. Kahlig ◽  
Joseph K. Yu ◽  
Thomas O’Hara ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Sodium Current ◽  
Somatic Mosaicism ◽  
Mendelian Inheritance ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Causal Mechanism ◽  
Long Qt ◽  
Gene Panel Testing ◽  
Qt Syndrome

Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

Long QT syndrome and associated gene mutation carriers in Japanese children: results from ECG screening examinations

2009 ◽  
Vol 117 (12) ◽  
pp. 415-424 ◽  
Author(s):  
Kenshi Hayashi ◽  
Noboru Fujino ◽  
Katsuharu Uchiyama ◽  
Hidekazu Ino ◽  
Kenji Sakata ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
High Probability ◽  
Dominant Negative ◽  
Carrier Status ◽  
Japanese Children ◽  
Long Qt ◽  
Mutation Carriers ◽  
Qt Intervals ◽  
Qt Syndrome

LQTS (long QT syndrome) is caused by mutations in cardiac ion channel genes; however, the prevalence of LQTS in the general population is not well known. In the present study, we prospectively estimated the prevalence of LQTS and analysed the associated mutation carriers in Japanese children. ECGs were recorded from 7961 Japanese school children (4044 males; mean age, 9.9±3.0 years). ECGs were examined again for children who had prolonged QTc (corrected QT) intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined according to Schwartz's criteria, and ion channel genes were analysed. In vitro characterization of the identified mutants was performed by heterologous expression experiments. Three subjects were assigned to a high probability of LQTS (3.5≤ LQTS score), and eight subjects to an intermediate probability (1.0< LQTS score ≤3.0). Genetic analysis of these II subjects identified three KCNH2 mutations (M124T, 547–553 del GGCGGCG and 2311–2332 del/ins TC). In contrast, no mutations were identified in the 15 subjects with a low probability of LQTS. Electrophysiological studies showed that both the M124T and the 547–553 del GGCGGCG KCNH2 did not suppress the wild-type KCNH2 channel in a dominant-negative manner. These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (three in 7961), and that LQTS mutation carriers can be identified in at least 0.038% (one in 2653). Furthermore, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene-carrier status, as it may have been underestimated in the present study.

Neonatal Long QT Syndrome Due to a De Novo Dominant Negative hERG Mutation

2007 ◽  
Vol 16 (4) ◽  
pp. 416-412 ◽  
Author(s):  
Theresa A. Beery ◽  
Kerry A. Shooner ◽  
D. Woodrow Benson
Keyword(s):  
Long Qt Syndrome ◽  
De Novo ◽  
Sinus Bradycardia ◽  
Molecular Genetic ◽  
Ventricular Tachyarrhythmia ◽  
Dominant Negative ◽  
De Novo Mutation ◽  
Long Qt ◽  
Dominant Negative Mutation ◽  
Qt Syndrome

A 4-day-old girl with ventricular tachyarrhythmias, sinus bradycardia, and 2:1 atrioventricular block had prolongation of the QT interval. She was symptomatic with arching, gasping, and cyanosis presumably due to a life-threatening ventricular tachyarrhythmia such as torsades de pointes. Molecular genetic studies indicated a heterozygous, de novo, dominant negative mutation in hERG, a gene that encodes a protein in a potassium ion channel. The parents do not have the mutation. The patient’s clinical scenario was produced by the convergence of 3 events: a de novo mutation occurred in hERG, the mutation was dominant negative, and the action of the mutation resulted in neonatal long QT syndrome. The child was treated aggressively and is doing well at age 6 years.

Abstract 136: Novel Disease Analysis Using Long QT Syndrome-Specific Induced Pluripotent Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toru Egashira ◽  
Shinsuke Yuasa ◽  
Keiichi Fukuda
Keyword(s):  
Long Qt Syndrome ◽  
Field Potential ◽  
Dominant Negative ◽  
Heterozygous Mutation ◽  
Specific Information ◽  
Long Qt ◽  
Disease Phenotypes ◽  
Severe Arrhythmia ◽  
Qt Syndrome ◽  
Iks Channel

[Background] Although previous reports have indicated that long QT syndrome-specific iPS cells (LQTS-iPSCs)-derived cardiomyocytes recapitulated disease phenotypes, those patients were previously diagnosed with mutated channel profiles. In reality, most patients have no such specific information. To address whether iPSCs could be used for personalized disease characterization, we generated iPSCs from a sporadic LQTS patient with unknown disease cause. [Methods and Results] 1 We generated iPSCs from control (n = 2) and a patient with LQTS, and differentiated into cardiomyocytes through embryoid body (EB) formation. 2 Electrophysiological analysis of the LQTS-iPSCs-derived EBs using multi electrode array system revealed that the duration of the field potential (FPD) was markedly prolonged compared with the control (388.9 ± 44.3 msec vs 202.3 ± 16.3 msec, P<0.01). 3 We tested several drugs affecting QT prolongation to clarify the electrophysiological properties. The IKr blocker E4031 significantly prolonged FPD (% change 1.21 ± 0.02, P<0.01) and induced frequent severe arrhythmia, not only early-after depolarization (n = 8/16 vs n = 1/16) but also torsades de pointes-like arrhythmia, only in LQTS (n = 4/16 vs n = 0/16). The IKs blocker, chromanol 293B did not prolong FPD in LQTS but it significantly prolonged FPD in the control (% change 1.09 ± 0.04, NS vs 1.44 ± 0.07, P<0.01), suggesting the involvement of IKs disturbance in the patient. Isoproterenol induced ventricular tachycardia-like arrhythmia only in LQTS, which was blocked by propranolol. These data strongly suggested a functional impairment in the patient’s IKs channel; genotype analysis for KCNQ1 gene revealed a novel heterozygous mutation, 1893delC. 4 Patch clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channel through a trafficking deficiency. [Conclusions] LQTS-iPSCs-derived cardiomyocytes recapitulated the disease phenotypes, and they can be utilized for identification of the disease cause and genotype. This study demonstrated that iPSCs could be useful to characterize the disease, drug responses, diagnosis and genotyping in patients with sporadic LQTS, which in turn may facilitate medical therapies in the clinical settings.

scholarly journals A Dominant Negative Isoform of the Long QT Syndrome 1 Gene Product

1998 ◽  
Vol 273 (12) ◽  
pp. 6837-6843 ◽  
Author(s):  
Sophie Demolombe ◽  
Isabelle Baró ◽  
Yann Péréon ◽  
Jet Bliek ◽  
Raha Mohammad-Panah ◽  
...  
Keyword(s):  
Gene Product ◽  
Long Qt Syndrome ◽  
Dominant Negative ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of theKCNE1gene

2016 ◽  
Vol 173 (12) ◽  
pp. 2046-2061 ◽  
Author(s):  
Péter Major ◽  
István Baczkó ◽  
László Hiripi ◽  
Katja E. Odening ◽  
Viktor Juhász ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Rabbit Model ◽  
Dominant Negative ◽  
Long Qt ◽  
Transgenic Rabbit ◽  
Dominant Negative Mutation ◽  
Repolarization Reserve ◽  
Qt Syndrome

scholarly journals Dominant-Negative Control of cAMP-Dependent I Ks Upregulation in Human Long-QT Syndrome Type 1

2012 ◽  
Vol 110 (2) ◽  
pp. 211-219 ◽  
Author(s):  
Jordi Heijman ◽  
Roel L.H.M.G. Spätjens ◽  
Sandrine R.M. Seyen ◽  
Viola Lentink ◽  
Helma J.H. Kuijpers ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Negative Control ◽  
Dominant Negative ◽  
Syndrome Type ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals A Weak Dominant Negative Mutation of KCNQ1-G269S Affects PKA-Mediated Up-Regulation of IKs Channels and Causes Adrenergic Triggered Long QT Syndrome

2011 ◽  
Vol 27 (Supplement) ◽  
pp. OP60_3
Author(s):  
Jie Wu ◽  
Nobu Naiki ◽  
Wei-Guang Ding ◽  
Hiroshi Matsuura ◽  
Minoru Horie
Keyword(s):  
Long Qt Syndrome ◽  
Dominant Negative ◽  
Long Qt ◽  
Dominant Negative Mutation ◽  
Qt Syndrome
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