Dominant-Negative
            <i>KvLQT1</i>
            Mutations Underlie the LQT1 Form of Long QT Syndrome

Shalaby, Fouad; Lévesque, Paul; Yang, Wen-Pin; Little, Wayne A.; Conder, Mary Lee; Jenkins-West, Tonya; Blanar, Michael A.

doi:10.1161/01.cir.96.6.1733

Cited by 121 publications

(76 citation statements)

References 13 publications

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“…Both amino acids have hydrophobic side chains often found in the interior of folded proteins. Based on literature data, a substitution of leucine to phenylalanine may result in a mild functional deficit of the affected protein, as was reported for the mutation L272F in the KvLQT1 gene 43 and for the mutation (F193L) in the KCNQ1 gene 44 observed in two different forms of long QT syndrome. We speculate that the TTN:c.14563C4T (p L4855F) identified in this study may lead to a mild defect in titin function that became manifest in combination with the LMNA mutation.…”

Section: Discussionmentioning

confidence: 84%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

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Section: Discussionmentioning

confidence: 84%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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“…Some previously described disease-associated mutations in K þ channels have come to be recognized to be pathogenic because they produce truncated nonfunctional dominant inhibitory subunits. Such mutations in KCNQ1 (KvLQT1) 60 and KCNH2 (hERG) 61 genes were recognized to produce dominant 'channelopathies' underlying Long QT syndromes. Similar mutants that truncate KCNQ2 and KCNQ3 are responsible for benign familial neonatal convulsion (BFNC) types 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, dominant negative regulation of multimeric proteins by non-functional variants may be a general mechanism for the regulation of protein function with a proven potential to cause disease when perturbed. [60][61][62]69 Modulation by SK3-1B of functional SK channel expression in the brain is likely to have significant effects on electrical excitability. Since the family of SK channels plays an important role in defining the excitability profile of a neuron, the potential value of a dominant-negative regulatory SK3-1B subunit for both homeostasis and plasticity is apparent.…”

Section: Discussionmentioning

confidence: 99%

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

et al. 2003

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The small-conductance calcium-activated K þ channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa. We have identified a novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3. SK3-1B, mRNA is widely distributed in human tissues and is present at 20-60% of SK3 in the brain. The SK3-1B protein lacks the N-terminus and first transmembrane segment, and begins eight residues upstream of the second transmembrane segment. When expressed alone, SK3-1B did not produce functional channels, but selectively suppressed endogenous SK3 currents in the pheochromocytoma cell line, PC12, in a dominant-negative fashion. This dominant inhibitory effect extended to other members of the SK subfamily, but not to voltage-gated K þ channels, and appears to be due to intracellular trapping of endogenous SK channels. The effect of SK3-1B expression is very similar to that produced by expression of the rare SK3 truncation allele, SK3-D, found in a patient with schizophrenia. Regulation of SK3 and SK3-1B levels may provide a potent mechanism to titrate neuronal firing rates and neurotransmitter release in monoaminergic neurons, and alterations in the relative abundance of these proteins could contribute to abnormal neuronal excitability, and to the pathogenesis of schizophrenia.

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“…HERG lesions reduce outward K + (IKr) current; 25 SCN5A lesions increase inward plateau Na + current; 33,34 and KvLQT1 lesions reduce outward K + (IKs) current. 33,34 All 3 types of lesions prolong cardiac action potentials in LQTS.…”

Section: The Relationship Of the Molecular Lesion To The Arrhythmia Amentioning

confidence: 99%

“…33,34 All 3 types of lesions prolong cardiac action potentials in LQTS. When different mutants of each of these channels are studied in systems such as the Xenopus oocyte, a range of abnormalities in ion currents is observed, suggesting that the clinical manifestations of the disease may depend not just on the gene affected but on the specific mutation.…”

Section: The Relationship Of the Molecular Lesion To The Arrhythmia Amentioning

confidence: 99%

The Search for Novel Antiarrhythmic Strategies

Gambit¹

1998

Jpn Circ J

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he first 2 meetings of the Sicilian Gambit focused on a pathophysiologic approach to evaluate antiarrhythmic drugs in light of the electrophysiologic mechanisms for cardiac arrhythmias; 1,2 on the extent to which this approach was effective in identifying the most appropriate therapy for clinical arrhythmias; and on areas where further information was needed to provide rational directions for therapy. 3 The stimulus for the third Sicilian Gambit meeting (the subject of this report) was continued concern over the future of antiarrhythmic drug therapy, based on (1) the increased mortality reported with d-sotalol in the SWORD trial; 4 (2) the failure of amiodarone to reduce all-cause mortality in CAMIAT 5 , EMIAT 6 and CHF-STAT 7 ; and (3) the extent to which international differences in perceived needs and guidelines for drug development might reduce enthusiasm for drug discovery. Participating in the meeting were basic and clinical scientists, investigators involved in drug trials and representatives of regulatory and funding agencies.In the following pages we emphasize that (1) traditional modalities of antiarrhythmic drug development have reached a near-impasse; (2) new perspectives should, nonetheless, lead to novel antiarrhythmic approaches; (3) information derived from molecular technology should facilitate the identification of specific targets for pharmacologic intervention; (4) at least one condition, congenital long QT syndrome, may soon represent "proof of concept" of the linkage between molecular biology and novel treatment strategies; (5) common arrhythmias like atrial fibrillation and ventricular tachycardia and fibrillation may be amenable to a similar approach; and (6) new thinking on development of novel compounds must be complemented by innovative decisions in clinical trials. We stress, as well, that a major market for antiarrhythmic drug therapy still exists: the frequency of lethal ventricular tachyarrhythmias as well as of atrial fibrillation is such that therapies having widespread applicability at modest cost must be sought. RationaleEarly approaches to antiarrhythmic drug development involved the serendipitous identification of antiarrhythmic actions of natural compounds such as cinchona 8 or compounds synthesized for other applications such as procaine. 9 This was followed by synthesis of derivative molecules (respectively, quinidine 10 and procainamide 11 ) and their testing in animal models and in human subjects. Identification of a perceived benefit in human subjects (eg, suppression of ventricular premature depolarizations) could lead to a search for related molecules the effects of which might be more sustained, less toxic and/or more potent, or with properties that might be modified advantageously. These molecules also were tested in animal models for their antiarrhythmic efficacy and toxicity and, if they passed muster, were tested in patients. Shortcomings of this approach are that molecules thus identified tend to incorporate not only the potential benefits of the so-called paren...

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Dominant-Negative KvLQT1 Mutations Underlie the LQT1 Form of Long QT Syndrome

Abstract: In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I(Ks) current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

Cited by 121 publications

References 13 publications

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

The Search for Novel Antiarrhythmic Strategies

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