PhD Scientific Days 2025

Molecular Medicine I.

Identification of a Novel KCNA5 Variant Disrupting Kv1.5 Channel Function

Előadó neve

Csáki Réka, MSc

Neptun code

KA84WY

Előadó munkahelye

Department of Physiology, Semmelweis University

Előadó telefonszáma

+36304100841

Előadó e-mail címe

csakireka2@gmail.com

Az előadás címe

Identification of a Novel KCNA5 Variant Disrupting Kv1.5 Channel Function

Szerző(k) neve és munkahelye

Réka Csáki¹, Vasile Foris², Christina A. Eichstaedt³, Alice Dobolyi¹, Chandran Nagaraj², Michael Halank⁴, Ekkehard Grünig³, Horst Olschewski⁵, Andrea Olschewski⁶, Péter Enyedi¹

1: Department of Physiology, Semmelweis University
2: Division of Pulmonology, Department of Internal Medicine, Medical University of Graz
3: Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Laboratory for Molecular Diagnostics, Institute of Human Genetics, Heidelberg University
4: Medical Clinic I and Polyclinic I, University Hospital Carl Gustav Carus of the Technical University of Dresden
5: neumology & Experimental Medicine, Sigmund Freud Private University, Department of Infectious Diseases and Respiratory Medicine at Charité – Universitätsmedizin Berlin,
6: Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz

Bemutatás módja

Szóbeli

Szekció

Molecular Medicine I.

Language of the presentation

English

Preferred session

Molecular Medicine

Összefoglaló szövege

Introduction
Pulmonary arterial hypertension (PAH) is a severe condition marked by increased small arterial pressure and right heart failure. It may arise from dysfunctional ion channels in pulmonary arterial smooth muscle cells (PASMCs), leading to depolarization, increased vascular tone, and vessel wall remodeling. Potassium ion channels are key regulators of PASMC membrane potential. Previous studies have linked mutations in the voltage-gated K⁺ channel Kv1.5 to PAH. Targeted genetic screening of our international PAH database identified several previously unreported Kv1.5 mutations.
Aims
Our experiments aim to clarify how altered K⁺ channel function contributes to PAH development. In this study we examined how the identified Kv1.5 mutations affect channel function.
Methods
Six identified Kv1.5 channel mutant clones were generated and expressed in Xenopus oocyte and HEK cell model systems. Their electrophysiological properties were studied by two-electrode voltage clamp and patch clamp measurements.
Results
Our findings indicate that among the six variants analysed only the Gly435Arg missense variant showed a significant reduction of 87±1.3% in whole-cell current compared to the wild-type (WT) channel. This variant was also characterized by slower activation and inactivation kinetics. In single channel recordings, conductance remained unaltered, while mutant mean open probability was reduced by at least 50% compared to WT.We hypothesize that the introduced positive charge of arginine may affect channel gating. The Gly435Arg variant was identified in a heterozygous form in a female patient with idiopathic PAH. To investigate whether the mutation has a dominant-negative effect on the channel function, WT and Gly435Arg subunits were linked as dimers to study the effect of the mutation under defined heterozygous conditions. We found a 53±3% reduction in heterotetrameric whole cell current.
Conclusion
This study provides the first evidence of a functionally significant KCNA5 gene variant that markedly impairs Kv1.5 channel function, potentially contributing to the pathogenesis of PAH.
Funding
Supported by the EKÖP-2024-41 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund, by SE250+ excellence PhD scholarship and by the NKFIH TKP2021-EGA-24.

University

Semmelweis University

Supervisor

Péter Enyedi M.D., D.Sc

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

phd.section.field

in doctoral studies after complex exam (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem hagyta jóvá

Előadó

7416

Start

16:00

End

16:15