Next Issue
Volume 13, December
Previous Issue
Volume 13, June
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
0.6
Journals
Cardiogenetics
Volume 13
Issue 3
share announcement

Cardiogenetics, Volume 13, Issue 3 (September 2023) – 3 articles

Cover Story (view full-size image): The hyperpolarization-activated ‘funny current’ (If) is a key player in the pacemaker activity of the sinus node. It flows through ion channels encoded by the HCN4 gene and contributes to the spontaneous diastolic depolarization of the sinus node cells. Patients carrying the heterozygous A414G mutation in HCN4 typically present with moderate-to-severe sinus bradycardia. Our in vitro patch clamp experiments demonstrate that the A414G mutation affects the voltage dependence of the If channels in such a way that less channels are active in the voltage range of diastolic depolarization. Our subsequent in silico experiments, based on our data acquired in vitro, show that diastolic depolarization is significantly slowed down by the A414G mutation, in particular under vagal tone and in the presence of atrial load, explaining the clinically observed sinus bradycardia. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
18 pages, 5312 KiB  
Article
Functional Characterization of the A414G Loss-of-Function Mutation in HCN4 Associated with Sinus Bradycardia
by Arie O. Verkerk and Ronald Wilders
Cardiogenetics 2023, 13(3), 117-134; https://doi.org/10.3390/cardiogenetics13030012 - 04 Aug 2023
Viewed by 1583
Abstract
Patients carrying the heterozygous A414G mutation in the HCN4 gene, which encodes the HCN4 protein, demonstrate moderate to severe bradycardia of the heart. Tetramers of HCN4 subunits compose the ion channels in the sinus node that carry the hyperpolarization-activated ‘funny’ current (If [...] Read more.
Patients carrying the heterozygous A414G mutation in the HCN4 gene, which encodes the HCN4 protein, demonstrate moderate to severe bradycardia of the heart. Tetramers of HCN4 subunits compose the ion channels in the sinus node that carry the hyperpolarization-activated ‘funny’ current (If), also named the ‘pacemaker current’. If plays an essential modulating role in sinus node pacemaker activity. To assess the mechanism by which the A414G mutation results in sinus bradycardia, we first performed voltage clamp measurements on wild-type (WT) and heterozygous mutant HCN4 channels expressed in Chinese hamster ovary (CHO) cells. These experiments were performed at physiological temperature using the amphotericin-perforated patch-clamp technique. Next, we applied the experimentally observed mutation-induced changes in the HCN4 current of the CHO cells to If of the single human sinus node cell model developed by Fabbri and coworkers. The half-maximal activation voltage V1/2 of the heterozygous mutant HCN4 current was 19.9 mV more negative than that of the WT HCN4 current (p < 0.001). In addition, the voltage dependence of the heterozygous mutant HCN4 current (de)activation time constant showed a −11.9 mV shift (p < 0.001) compared to the WT HCN4 current. The fully-activated current density, the slope factor of the activation curve, and the reversal potential were not significantly affected by the heterozygous A414G mutation. In the human sinus node computer model, the cycle length was substantially increased, almost entirely due to the shift in the voltage dependence of steady-state activation, and this increase was more prominent under vagal tone. The introduction of a passive atrial load into the model sinus node cell further reduced the beating rate, demonstrating that the bradycardia of the sinus node was even more pronounced by interactions between the sinus node and atria. In conclusion, the experimentally identified A414G-induced changes in If can explain the clinically observed sinus bradycardia in patients carrying the A414G HCN4 gene mutation. Full article
►▼ Show Figures

Figure 1

4 pages, 197 KiB  
Editorial
Unraveling the Genetic and Epigenetic Complexities of Hereditary Aortic Diseases and the Breakthroughs of Precision Medicine: An Editorial
by Fares Awa, Mays Tawayha and Wassim Mosleh
Cardiogenetics 2023, 13(3), 113-116; https://doi.org/10.3390/cardiogenetics13030011 - 18 Jul 2023
Viewed by 1348
Abstract
The field of genetics in cardiovascular disease has introduced new possibilities for understanding the fundamental causes of aortic diseases [...] Full article
(This article belongs to the Special Issue Advanced Research on Inherited Aortic Diseases)
7 pages, 1018 KiB  
Case Report
GMDS Intragenic Deletions Associate with Congenital Heart Disease including Ebstein Anomaly
by Shirley M. Lo-A-Njoe, Eline A. Verberne, Lars T. van der Veken, Eric Arends, J. Peter van Tintelen, Alex V. Postma and Mieke M. van Haelst
Cardiogenetics 2023, 13(3), 106-112; https://doi.org/10.3390/cardiogenetics13030010 - 06 Jul 2023
Viewed by 1607
Abstract
Ebstein anomaly is a rare heterogeneous congenital heart defect (CHD) with a largely unknown etiology. We present a 6-year-old girl with Ebstein anomaly, atrial septum defect, hypoplastic right ventricle, and persistent left superior vena cava who has a de novo intragenic ~403 kb [...] Read more.
Ebstein anomaly is a rare heterogeneous congenital heart defect (CHD) with a largely unknown etiology. We present a 6-year-old girl with Ebstein anomaly, atrial septum defect, hypoplastic right ventricle, and persistent left superior vena cava who has a de novo intragenic ~403 kb deletion of the GDP-mannose 4,6-dehydratase (GMDS) gene. GMDS is located on chromosome 6p25.3 and encodes the rate limiting enzyme in GDP-fucose synthesis, which is used to fucosylate many proteins, including Notch1, which plays a critical role during mammalian cardiac development. The GMDS locus has sporadically been associated with Ebstein anomaly (large deletion) and tetralogy of Fallot (small deletion). Given its function and the association with CHD, we hypothesized that loss-of-function of, or alterations in, GMDS could play a role in the development of Ebstein anomaly. We collected a further 134 cases with Ebstein anomaly and screened them for genomic aberrations of the GMDS locus. No additional GMDS genomic aberrations were identified. In conclusion, we describe a de novo intragenic GMDS deletion associated with Ebstein anomaly. Together with previous reports, this second case suggests that GMDS deletions could be a rare cause for congenital heart disease, in particular Ebstein anomaly. Full article
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-3
Previous Issue
Next Issue
Back to TopTop