Rare DCM associated variants in pre-miR-208a disrupt miRNA maturation and function

Heart failure (HF) is a life threatening cardiac condition, which is defined as the inability of the heart to pump sufficient blood to meet the body’s demands. One of the major causes of HF are diseases of the heart muscle, so-called cardiomyopathies. In dilated cardiomyopathy (DCM) the heart is enlarged (dilated) and its pumping ability is reduced. DCM is frequently inherited and often caused by mutations (genetic variants) in genes that are essential for heart function. However, despite extensive research, a clear genetic cause can only be identified in about 30–40% of families affected by DCM.

To better understand the families in whom no genetic cause has yet been found (genetically unresolved), we studied a specific class of regulatory RNA molecules called microRNAs (miRNAs). These are very small, ~22-nucleotide long, RNA molecules that control protein production and thereby influence nearly every process in the cell. We focused on two miRNAs (miR-208a and miR-208b) known to play an important role in regulating the heart’s ability to contract. We examined 1640 unresolved DCM cases for mutations in these miRNAs.

We identified two mutations (+42G>T and +68G>T) in miR-208a to alter the secondary molecular structure of this miRNA. Laboratory experiments showed that these mutations also lead to lower expression levels and reduced function of this miRNA. Given the established role of miR-208a in regulating cardiac contractility, our findings suggest that these variants may contribute to the development of DCM in these patients. This provides further genetic insight into the causes for DCM for genetically unresolved cases.

Translated by Yolan Reckman and Ruth Biller

Authors: Yolan J. Reckman, Jan Haas, Ingeborg van der Made, Simon G. Williams, Iria Gomez Diaz, Mohammed Akhtar, Jens Mogensen, Torsten B. Rasmussen, Eric Villard, Philippe Charron, Perry Elliott, Bernard D. Keavney, Lorenzo Monserrat, Yigal M. Pinto, Benjamin Meder, Anke J. Tijsen.

Publication: Hum Mol Genet. 2025 Jul 3;34(14):1216-1226. doi: 10.1093/hmg/ddaf069.