Genomic and molecular evidence that the LncRNA DSP-AS1 modulates desmoplakin expression
Luisa Foco1, Marzia De Bortoli2, Fabiola Del Greco M2
1Eurac Research, Institute for Biomedicine, Via Volta 21, Bolzano, 39100, Italy. luisa.foco@eurac.edu.
Human Genetics
|July 30, 2025
Summary
Common genetic variants in desmosomal genes, like Desmoplakin (DSP), are linked to cardiac conduction traits. A specific DSP variant influences QRS duration, potentially through DSP-AS1 lncRNA, offering new therapeutic avenues for heart conditions.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genomics and Bioinformatics
Background:
- Cardiac desmosomes are crucial for cardiomyocyte mechanical coupling; mutations in desmosomal genes cause arrhythmogenic cardiomyopathy.
- Mendelian diseases share genetic architecture with common complex traits, suggesting common variants may influence cardiac function.
- Understanding the genetic basis of cardiac conduction traits is vital for diagnosing and treating heart conditions.
Purpose of the Study:
- To investigate associations between common variants in desmosomal genes (DSP, JUP, PKP2, DSG2, DSC2) and cardiac conduction traits (P-wave, PR, QRS, QT intervals).
- To explore the functional and causal relationship between genetic variants, desmosomal gene expression, and cardiac traits.
- To identify potential therapeutic targets for conditions related to desmoplakin dysfunction.
Main Methods:
- Genotype imputation and association analysis of five desmosomal genes with ECG intervals in 4342 CHRIS study participants.
- Functional annotation and interrogation of GWAS resources, followed by two-sample Mendelian randomization (MR) analysis.
- In vitro validation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to assess gene regulation.
Main Results:
- A Desmoplakin (DSP) variant (rs2744389) was significantly associated with QRS duration, replicated in the MICROS study.
- Mendelian randomization identified a causal effect of DSP-AS1 antisense long non-coding RNA on DSP expression and QRS duration.
- Downregulation of DSP-AS1 in hiPSC-CMs led to increased DSP mRNA and protein levels, indicating a regulatory role.
Conclusions:
- Common variants in desmosomal genes, particularly DSP, are associated with cardiac conduction traits in the general population.
- DSP-AS1 plays a regulatory role in DSP expression, suggesting it as a potential therapeutic target for desmoplakin-related disorders.
- This study highlights the interplay between lncRNAs, desmosomal genes, and cardiac electrophysiology, opening avenues for novel treatments.
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