ArticleJournal of molecular and cellular cardiology2010
Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.
Article in Journal of molecular and cellular cardiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 87 citations in OpenAlex.
- Review
- Developmental roles of natriuretic peptides and their receptors.Cells & development · 2023Review
- Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms.International journal of molecular sciences · 2023Review
- Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel.Orphanet journal of rare diseases · 2022Article
- Genetic and non-genetic risk factors associated with atrial fibrillation.Life sciences · 2022Review
- Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.JCI insight · 2022Article
- Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation.Cardiovascular research · 2021Review
- Atrial Fibrillation in Inherited Channelopathies.Cardiac electrophysiology clinics · 2021Review
- Genetics of Atrial Fibrillation.Journal of the American Heart Association · 2018Review
- Mechanisms and Drug Development in Atrial Fibrillation.Pharmacological reviews · 2018Review
- Atrial fibrillation symptom profiles associated with healthcare utilization: A latent class regression analysis.Pacing and clinical electrophysiology : PACE · 2018Article
- Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice.Circulation research · 2017Article
- EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication.Heart rhythm · 2017Review
- EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2016Article
- EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: Definition, characterisation, and clinical implication.Journal of arrhythmia · 2016Article
- Atrial fibrillation.Nature reviews. Disease primers · 2016Article
- TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians.Cardiovascular research · 2016Article
- The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics: Is Personalized Therapy in Sight?Journal of cardiovascular pharmacology · 2016Review
- Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart.International journal of legal medicine · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in multiple genes have been implicated in familial atrial fibrillation (AF), but the underlying mechanisms, and thus implications for therapy, remain ill-defined. Among 231 participants in the Vanderbilt AF Registry, we found a mutation in KCNQ1 (encoding the alpha-subunit of slow delayed rectifier potassium current [I(Ks)]) and separately a mutation in natriuretic peptide precursor A (NPPA) gene (encoding atrial natriuretic peptide, ANP), both segregating with early onset lone AF in different kindreds. The functional effects of these mutations yielded strikingly similar I(Ks) "gain-of-function." In Chinese Hamster Ovary (CHO) cells, coexpression of mutant KCNQ1 with its ancillary subunit KCNE1 generated approximately 3-fold larger currents that activated much faster than wild-type (WT)-I(Ks). Application of the WT NPPA peptide fragment produced similar changes in WT-I(Ks), and these were exaggerated with the mutant NPPA S64R peptide fragment. Anantin, a competitive ANP receptor antagonist, completely inhibited the changes in I(Ks) gating observed with NPPA S64R. Computational simulations identified accelerated transitions into open states as the mechanism for variant I(Ks) gating. Incorporating these I(Ks) changes into computed human atrial action potentials (AP) resulted in 37% shortening (120 vs. 192 ms at 300 ms cycle length), reflecting loss of the phase II dome which is dependent on L-type calcium channel current. We found striking functional similarities due to mutations in KCNQ1 and NPPA genes which led to I(Ks) "gain-of-function", atrial AP shortening, and consequently altered calcium current as a common mechanism between diverse familial AF syndromes.
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