PUBLICATION
A NOVEL PATHOGENIC ROLE FOR GALECTIN-3 IN EARLY DISEASE STAGES OF ARRHYTHMOGENIC CARDIOMYOPATHY
- Authors
- Cason, M., Celeghin, R., Marinas, M.B., Beffagna, G., DellaBarbera, M., Rizzo, S., Remme, C.A., Bezzina, C., Tiso, N., Bauce, B., Thiene, G., Basso, C., Pilichou, K.
- ID
- ZDB-PUB-210416-10
- Date
- 2021
- Source
- Heart rhythm 18(8): 1394-1403 (Journal)
- Registered Authors
- Tiso, Natascia
- Keywords
- LGALS3, Wnt signaling, arrhythmogenic cardiomyopathy, gene expression, inflammation, transgenic models
- MeSH Terms
-
- Animals
- Arrhythmogenic Right Ventricular Dysplasia/genetics*
- Arrhythmogenic Right Ventricular Dysplasia/metabolism
- DNA/genetics*
- DNA Mutational Analysis
- Disease Models, Animal
- Galectin 3/genetics*
- Galectin 3/metabolism
- Mice
- Mice, Transgenic
- Mutation*
- Phenotype
- PubMed
- 33857645 Full text @ Heart Rhythm
Citation
Cason, M., Celeghin, R., Marinas, M.B., Beffagna, G., DellaBarbera, M., Rizzo, S., Remme, C.A., Bezzina, C., Tiso, N., Bauce, B., Thiene, G., Basso, C., Pilichou, K. (2021) A NOVEL PATHOGENIC ROLE FOR GALECTIN-3 IN EARLY DISEASE STAGES OF ARRHYTHMOGENIC CARDIOMYOPATHY. Heart rhythm. 18(8):1394-1403.
Abstract
Background Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations, whose pathogenesis remains incompletely understood.
Objective To identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models.
Methods RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice over-expressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases.
Results Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacological inhibition of Lgals3 in zebrafish reduced Wnt and TGFβ signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the GAL3 release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions.
Conclusions GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping