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Foco, L.* ; De Bortoli, M.* ; Del Greco M, F.* ; Frommelt, L.S.* ; Volani, C.* ; Riekschnitz, D.A.* ; Motta, B.M.* ; Fuchsberger, C.* ; Delerue, T. ; Völker, U.* ; Huan, T.* ; Gögele, M.* ; Winkelmann, J. ; Dörr, M.* ; Levy, D.* ; Waldenberger, M. ; Teumer, A.* ; Pramstaller, P.P.* ; Rossini, A.* ; Pattaro, C.*

Genomic and molecular evidence that the LncRNA DSP-AS1 modulates desmoplakin expression.

Hum. Genet., DOI: 10.1007/s00439-025-02761-x (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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Cardiac desmosomes are specialized cell junctions responsible for cardiomyocytes mechanical coupling. Mutation in desmosomal genes cause autosomal dominant and recessive familial arrhythmogenic cardiomyopathy. Motivated by evidence that Mendelian diseases share genetic architecture with common complex traits, we assessed whether common variants in any desmosomal gene were associated with cardiac conduction traits in the general population. We analysed data of N = 4342 Cooperative Health Research in South Tyrol (CHRIS) study participants. We tested associations between genotype imputed variants covering the five desmosomal genes Desmoplakin (DSP), junction plakoglobin (JUP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), and P-wave, PR, QRS, and QT electrocardiographic intervals, using linear mixed models. Functional annotation and interrogation of publicly available genome-wide association study resources implicated potential connection with antisense long non-coding RNAs (lncRNAs), DNA methylation sites, and complex traits. Causality was tested via two-sample Mendelian randomization (MR) analysis and validated with functional in vitro follow-up in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). DSP variant rs2744389 was associated with QRS (P = 3.5 × 10-6), with replication in the Microisolates in South Tyrol (MICROS) study (n = 636; P = 0.010). Observing that rs2744389 was associated with DSP-AS1 antisense lncRNA but not with DSP expression in multiple Genotype-Tissue Expression (GTEx) v8 tissues, we conducted two-sample Mendelian randomization analyses that identified causal effects of DSP-AS1 on DSP expression (P = 6.33 × 10-5; colocalization posterior probability = 0.91) and QRS (P = 0.015). In hiPSC-CMs, DSP-AS1 expression downregulation through a specific GapmerR matching sequence led to significant DSP upregulation at both mRNA and protein levels. The evidence that DSP-AS1 has a regulatory role on DSP opens the venue for further investigations on DSP-AS1's therapeutic potential for conditions caused by reduced desmoplakin production.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Loci; Participants; Variance; Genotype; Pathway
ISSN (print) / ISBN 0340-6717
e-ISSN 1432-1203
Journal Human Genetics
Publisher Springer
Publishing Place One New York Plaza, Suite 4600, New York, Ny, United States
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Neurogenomics (ING)
Grants Department of Innovation
South Tyrolean Sparkasse Foundation
Ministry of Health of the Autonomous Province of Bolzano/Bozen - South Tyrol
Bioresource Impact Factor
Healthcare System of the Autonomous Province of Bolzano/Bozen - South Tyrol
Joint Project Alto Adige-SNSF (Italy-Switzerland)