PhD Scientific Days 2026

Poster Session 2.C - Molecular Medicine

Functional and Structural Analysis of a Rare Kv1.5 Mutation Linked to Pulmonary Arterial Hypertension

Előadó neve

Csáki, Réka, MSc

Előadó munkahelye

Department of Physiology, Semmelweis University

Előadó telefonszáma

06304100841

Előadó e-mail címe

csaki.reka@phd.semmelweis.hu

Az előadás címe

Functional and Structural Analysis of a Rare Kv1.5 Mutation Linked to Pulmonary Arterial Hypertension

Szerző(k) neve és munkahelye

Réka Csáki¹, Vasile Foris², Christina A. Eichstaedt³, János Almássy⁴, Alice Dobolyi⁴, Balázs Tóth⁵, Michael Halank⁶, Horst Olschewski⁷, Andrea Olschewski⁸, Péter Enyedi⁴

1: Department of Physiology, Semmelweis University
2: Division of Respiratory Medicine, Medical University of Graz, Graz, Austria
3: Center for Pulmonary Hypertension, Thoraxklinik, Heidelberg University Hospital, TLRC, DZL, Heidelberg, Germany
4: Department of Physiology, Semmelweis University, Budapest, Hungary
5: Department of Biochemistry, Semmelweis University, Budapest, Hungary
6: Pulmonology, University Hospital Dresden, TU Dresden, Germany
7: Infectious Diseases and Respiratory Medicine, Charité, Berlin, Germany
8: Lung Vascular Research Group, Medical University of Graz, Graz, Austria

Bemutatás módja

Poszter

Szekció

Poster Session 2.C - Molecular Medicine

Language of the presentation

English

Preferred session

Molecular Medicine

Összefoglaló szövege

Introduction
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with diverse genetic backgrounds, including mutations affecting ion channels such as Kv1.5. This channel plays a key role in regulating pulmonary arterial smooth muscle cell (PASMC) membrane potential and proliferation, and its dysfunction has been linked to PAH pathogenesis. However, the function of such Kv1.5 variants is poorly discovered.
Aims
Therefore, we aimed to characterize the functional impact of a new Kv1.5 mutation and to explore the structural mechanisms underlying the observed channel dysfunction.
Method
Targeted sequencing of 540 PAH patients identified rare Kv1.5 variants, which were expressed in Xenopus laevis oocytes, and analyzed using two-electrode voltage clamp and patch clamp techniques. PASMC proliferation assays were performed to assess cellular effects. Structural analysis was carried out using an AlphaFold-based model, complemented by targeted mutagenesis to dissect the role of local charge and flexibility.
Results
Among the tested variants, G435R showed a marked loss-of-function (~87% current reduction) with shortened mean open time, indicating impaired gating, while protein expression remained unaltered. Heterozygous concatemer constructs displayed reduced currents (~53%) too. In PASMCs, wild-type Kv1.5 overexpression suppressed proliferation, whereas G435R promoted a proliferative phenotype. Structural modelling localized the mutation to the S5 helix near the S4-S5 linker. To find out if the charge or altered flexibility of the arginine matters in G435R phenotype, we exchanged R and G in positions 432 and 435 resulting in RG (WT), RR, GG, and GR constructs. In addition alanine substitution was also generated at position 435. As expected, RR showed ~10% of WT current, the GG partially restored the function (46%), and GR caused a near-complete loss-of-function (<1%), while alanine substitution had no effect.
Conclusion
The G435R variant causes severe Kv1.5 channel dysfunction by disrupting channel gating, primarily driven by altered local charge rather than reduced flexibility of the structure. Combined electrophysiological, structural and cellular data support its pathogenic role in PAH and provide mechanistic insight into Kv1.5 regulation.
Funding
Supported by the SE250+ Excellence PhD Scholarship, Predoctoral Scholarship, and NKFIH TKP2021-EGA-24.

University

Semmelweis University

Supervisor

Prof. Péter Enyedi

Publication of my abstract

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

phd.section.field

after finishing doctoral studies with absolutorium (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7416

Start

18:18

End

18:21