ERA-CVD - Scale

SCALE: Single Cardiomyocyte ALlelic imbalancE in hypertrophic cardiomyopathy


Consortium partners:

University Medical Center Utrecht, Utrecht, The Netherlands
Magdalena Harakalova (consortium leader, PI), Frank van Steenbeek (PI), Jiayi Pei (Postdoc).

Netherlands Heart Institute
Fleur Meijers (project manager).

Hannover Medical School (MHH), Hannover, Germany
Judith Montag (PI), Alexander Frick (PhD).

University Hospital Puerta de Hierro Majadahonda, Madrid, Spain
Fernando Dominguez (PI), Enrique Lara (PI).

The Hospital University Institute-Institute of Cardiometabolism and Nutrition (IHU-ICAN), Paris, France
Eric Villard (PI), Vincent Fontaine (Postdoc), Pierre Bobin (Postdoc).



Hypertrophic cardiomyopathy (HCM) is mainly caused by heterozygous mutations in sarcomeric genes. Patients express both, the wild-type and the mutated allele. A SCALE consortium member showed that the fraction of mutated mRNA differs between neighboring cardiomyocytes (CM) in cardiac tissue. This cell-to-cell allelic imbalance is associated with a contractile imbalance between the CMs – mosaicism in the myocardium that may contribute to the HCM phenotype. To address the cause and consequence of cell-to-cell allelic imbalance, we will mainly focus on single CMs originating from HCM patients with different mutations. First, we will study the hypothesis that the percentage of the mutant alleles is associated with altered gene expression (Aim 1). For this purpose, (single-cell) full-length RNA sequencing using short and long reads will be performed on individual CMs from 2D- and 3D-cultures of induced pluripotent stem cells. We will correlate the percentage of reads supporting the mutated allele per cell to its transcriptional profile. Next, we address the underlying mechanisms of allelic imbalance (Aim 2). We will perform chromatin immunoprecipitation sequencing on CMs to evaluate the chromatin regulation effect on allelic expression, and analyze the potential effects of alternative splicing. Lastly, we aim to modulate the cell-to-cell allelic imbalance to minimize functional mosaicism (Aim 3). To achieve this we will interfere with cultured CMs using compounds that might revert the allelic imbalance as possible treatment options.



Previous consortium meetings:

2022, March 3 - Consortium meeting

2021, November 24 - Bi-annual consortium meeting

2021, May 31 - Consortium meeting

2021, April 29 - Bi-annual consortium meeting

2020, September 8 – Consortium meeting

2020, October 29 – Consortium meeting


Principal investigator(s): Magdalena Harakalova

Started in: 2019

Tel: 088-2333600      E-mail:      Twitter: @nl_heart      Facebook: @netherlandsheartinstitute