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

Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) defined by ventricular dilatation and systolic dysfunction. Although microRNAs (miRNAs) are known to affect HF development, little is known about the contribution of genetic variants in miRNAs or their precursors to the susceptibility or pathogenesis of DCM. We screened 1640 DCM cases for variants in cardiac miR-208a and miR-208b and their precursors. We identified four variants in the miR-208a pre-miRNA, which are present at very low frequencies in the general population. Two of these variants (+42G > T and +68G > T) alter a highly conserved nucleotide and the predicted pre-miRNA secondary structure. Both variants result in reduced mature miR-208a levels in overexpression experiments. The variant +42G > T also increased pre-miR-208a levels in these experiments, which indicates a maturation deficiency. Co-transfection of the overexpression constructs with a luciferase construct containing six miRNA binding sites revealed that both variants also impair repression of luciferase expression by miR-208a, indicative of also a loss of miR208a function. Together this indicates that these DCM-associated variants impair formation of mature miR208a. Combined with the role of miR-208a in cardiac contractility this suggests that variants +42G > T and +68G > T in pre-miR-208a may contribute to the DCM phenotype observed in these patients.

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Publication Details

Journal
Human Molecular Genetics
Published
2025-05-06
DOI
https://doi.org/10.1093/hmg/ddaf069
Primary Topic
MicroRNA in disease regulation
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Iván Dı́az, Perry Elliott, Simon G. Williams, Lorenzo Monserrat et al.
Human Molecular Genetics
MicroRNA in disease regulation
article

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

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

Abstract

Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) defined by ventricular dilatation and systolic dysfunction. Although microRNAs (miRNAs) are known to affect HF development, little is known about the contribution of genetic variants in miRNAs or their precursors to the susceptibility or pathogenesis of DCM. We screened 1640 DCM cases for variants in cardiac miR-208a and miR-208b and their precursors. We identified four variants in the miR-208a pre-miRNA, which are present at very low frequencies in the general population. Two of these variants (+42G > T and +68G > T) alter a highly conserved nucleotide and the predicted pre-miRNA secondary structure. Both variants result in reduced mature miR-208a levels in overexpression experiments. The variant +42G > T also increased pre-miR-208a levels in these experiments, which indicates a maturation deficiency. Co-transfection of the overexpression constructs with a luciferase construct containing six miRNA binding sites revealed that both variants also impair repression of luciferase expression by miR-208a, indicative of also a loss of miR208a function. Together this indicates that these DCM-associated variants impair formation of mature miR208a. Combined with the role of miR-208a in cardiac contractility this suggests that variants +42G > T and +68G > T in pre-miR-208a may contribute to the DCM phenotype observed in these patients.

Human Molecular GeneticsVol. 34(14)
Universidade da Coruña (ES), Inserm (FR), Aarhus University (DK), Heidelberg University (DE), Odense University Hospital (DK), University Hospital Heidelberg (DE), Aarhus University Hospital (DK), University of Manchester (GB), Sorbonne Université (FR), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), University College Hospital at Westmoreland Street (GB), Pitié-Salpêtrière Hospital (FR), Medical Solutions (GB), ERN GUARD-Heart (NL), Unité de recherche sur les maladies cardiovasculaires et métaboliques (FR), NIHR Manchester Biomedical Research Centre (GB), University College London (GB)
Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, European Commission, ZonMw, Hartstichting, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Medical Research Council, HORIZON EUROPE European Innovation Council
Good health and well-being
Openalex Percentile: Top 87%
MicroRNA in disease regulation
DOIOpen Access PDFOpenAlex
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