Nocturnal Atrial Fibrillation Caused by Mutation in KCND2 , Encoding Pore-Forming (α) Subunit of the Cardiac Kv4.2 Potassium Channel

Abstract

Background: Paroxysmal atrial fibrillation (AF) can be caused by gain-of-function mutations in genes, encoding the cardiac potassium channel subunits KCNJ2 , KCNE1 , and KCNH2 that mediate the repolarizing potassium currents I k1 , I ks , and I kr , respectively. Methods: Linkage analysis, whole-exome sequencing, and Xenopus oocyte electrophysiology studies were used in this study. Results: Through genetic studies, we showed that autosomal dominant early-onset nocturnal paroxysmal AF is caused by p.S447R mutation in KCND2 , encoding the pore-forming (α) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, along with Kv4.3, contributes to the cardiac fast transient outward K + current, I to . I to underlies the early phase of repolarization in the cardiac action potential, thereby setting the initial potential of the plateau phase and governing its duration and amplitude. In Xenopus oocytes, the mutation increased the channel’s inactivation time constant and affected its regulation: p.S447 resides in a protein kinase C (PKC) phosphorylation site, which normally allows attenuation of Kv4.2 membrane expression. The mutant Kv4.2 exhibited impaired response to PKC; hence, Kv4.2 membrane expression was augmented, enhancing potassium currents. Coexpression of mutant and wild-type channels (recapitulating heterozygosity in affected individuals) showed results similar to the mutant channel alone. Finally, in a hybrid channel composed of Kv4.3 and Kv4.2, simulating the mature endogenous heterotetrameric channel underlying I to , the p.S447R Kv4.2 mutation exerted a gain-of-function effect on Kv4.3. Conclusions: The mutation alters Kv4.2’s kinetic properties, impairs its inhibitory regulation, and exerts gain-of-function effect on both Kv4.2 homotetramers and Kv4.2-Kv4.3 heterotetramers. These effects presumably increase the repolarizing potassium current I to , thereby abbreviating action potential duration, creating arrhythmogenic substrate for nocturnal AF. Interestingly, Kv4.2 expression was previously shown to demonstrate circadian variation, with peak expression at daytime in murine hearts (human nighttime), with possible relevance to the nocturnal onset of paroxysmal AF symptoms in our patients. The atrial-specific phenotype suggests that targeting Kv4.2 might be effective in the treatment of nocturnal paroxysmal AF, avoiding adverse ventricular effects.

Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

“…1 D). Gain-of-function variants in KCND2 have been implicated in nocturnal atrial fibrillation [ 37 ]. The nocturnal occurrence of symptoms was attributed to the circadian variation of Kv4.2 in murine hearts with a substantial 2-fold change in expression between night and day [ 38 ].…”

A tissue-aware machine learning framework enhances the mechanistic understanding and genetic diagnosis of Mendelian and rare diseases

“…We analyzed data from patients suffering from rare diseases that manifest in specific tissues. Patients were previously genetically diagnosed via exome sequencing and subsequent analysis as previously described 70–73 . The data per patient was de-identified, and variants were filtered as follows: kept variants with call quality at least 20.0 in cases or at least 20.0 in controls AND outside top 5.0% most exonically variable 100base windows in healthy public genomes (1000 genomes). excluded variants that were observed with an allele frequency greater than or equal to 0.5% of the genomes in the 1000 genomes project OR greater than or equal to 0.5% of the NHLBI ESP exomes (All); or greater than or equal to 0.5% of the ExAC Frequency; or greater than or equal to 0.5% of the gnomAD Frequency; or filter variants unless established pathogenic common variant. kept variants (up to 20 bases into intron) that were experimentally observed to be associated with a phenotype: Pathogenic, possibly Pathogenic or disease-associated according to HGMD; or clinically relevant variants from CentoMD; or frameshift, in-frame indel, or stop codon change, or missense, or predicted deleterious by having CADD score > 15.0; or predicted to disrupt splicing by MaxEntScan; or within 2 bases into intron. In case of dominant genes, kept variants which are associated with gain of function, or hemizygous, or heterozygous, or heterozygous-amb, or compound heterozygous, or homozygous, or heterozygous-alt, or haploinsufficient and occur in at least one of the Case samples at the variant level; and not variants which are associated with gain of function, or hemizygous, or heterozygous, or heterozygous-amb, or compound heterozygous, or homozygous, or heterozygous-alt, or haploinsufficient, and occur in at least one of the control samples at the variant level in the Control samples. …”

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

“…Although KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, CALM1, CALM2, and CALM3 genes are classified as definitely causal for LQTS [32], further studies are necessary to conclude the causality of the other genes for LQTS. Notably, it is also known that a part of LQTS, SQTS, BrS, and ERS share common genetic backgrounds and that some causal genes are also associated with other cardiac phenotypes, such as atrial fibrillation (AF) [33][34][35], and/or extra-cardiac phenotypes as shown in Table 1.…”

“…BrS (I Na ↓) [103] SEMA3A BrS (I Na ↓) [106] KCND2 ERS (I to ↑) [137], AF (I to ↑) [34]/Epilepsy (I A ↑) [147], ASD (I A ↑) [147] SLC4A3 SQTS (AE3↓) [81] KCND3…”