# Lamin variants cause cardiac arrhythmogenicity in Drosophila

## TL;DR

This study shows that different lamin gene variants cause unique heart rhythm problems in fruit flies, suggesting varied molecular causes for arrhythmia.

## Contribution

The study identifies distinct molecular pathways triggered by specific lamin variants in causing arrhythmia in Drosophila.

## Key findings

- Variants p.N210K and p.R264Q in Lamin C cause reduced heart rate and increased arrhythmia index in Drosophila.
- Taxol had opposing effects on arrhythmia in p.N210K and p.R264Q-expressing flies.
- LMNA variants trigger distinct molecular pathways leading to arrhythmogenic effects.

## Abstract

Atrial fibrillation (AF), the most common progressive cardiac arrhythmia, is associated with serious complications such as stroke and heart failure. Although common risk factors underlie AF onset, in 15% of the affected population, AF may have a genetic cause. Here, we investigated how LMNA variants cause cardiac arrhythmicity. Drosophila melanogaster strains were generated possessing the analogous variants in the Drosophila orthologue of human lamin A/C (LMNA), Lamin C (LamC). Heart wall movements in prepupae were recorded before (BTP) and after (ATP) tachypacing. ATP, flies expressing wild-type LamC, and the variants ΔN and p.R205W showed a significant reduction in heart rate (HR), but the arrhythmia index (AI) was not affected, compared to BTP. By contrast, those expressing p.N210K and p.R264Q showed a significant reduction in HR and increased AI, compared to BTP. p.N210K- and p.R264Q-expressing prepupae showed contrasting effects after pharmacological intervention with microtubule stabilizer taxol. Taxol attenuated the arrhythmogenicity in p.N210K-expressing prepupae, but aggravated it in p.R264Q-expressing prepupae. These findings suggest that different lamin variants trigger distinct molecular pathways that drive arrhythmogenic effects in Drosophila.

Summary: Atrial fibrillation-associated lamin variants trigger distinct molecular pathways that drive arrhythmogenic effects in Drosophila.