Heart disease in a mutant mouse model of spontaneous eosinophilic myocarditis maps to three loci
Related Experiment Video
Updated: Jan 6, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Nives Zimmermann1,2, William J Gibbons3, Shelli M Homan3
1Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Insights
A new mouse model with hypereosinophilic diseases (HD) develops eosinophilic myocarditis and heart disease. Genetic analysis identified three key loci (Emhd1, Emhd2, Emhd3) influencing the disease, offering insights into its complex inheritance.
Area of Science:
- Genetics
- Cardiology
- Immunology
Background:
- Heart disease (HD) is a significant cause of mortality in hypereosinophilic diseases.
- Limited animal models hinder understanding of eosinophil-mediated cardiac pathology.
- A novel A/J mouse mutant spontaneously develops hypereosinophilia and eosinophilic myocarditis.
Purpose of the Study:
- To investigate the genetic basis of heart disease in a novel hypereosinophilic mouse model.
- To identify genetic loci associated with eosinophil-mediated myocarditis and heart disease.
- To establish a valuable resource for studying eosinophil-associated cardiac pathology.
Main Methods:
- Generation and maintenance of the A/JHD mouse line.
- Crossbreeding A/JHD mice with other inbred strains to create recombinant populations.
- Linkage and haplotype analyses to identify disease-associated genetic loci.
Main Results:
- The heart disease (HD) trait in the A/JHD mouse model is heritable.
- Linkage analysis identified three significant loci: Emhd1 (recessive, chromosome 5), Emhd2 (dominant, chromosome 17), and Emhd3 (dominant, chromosome 17).
- Haplotype analysis defined the specific chromosomal intervals for Emhd1, Emhd2, and Emhd3.
Conclusions:
- The HD trait in this model is oligogenic with variable penetrance, influenced by multiple genetic and potentially non-genetic factors.
- The A/JHD mouse model is a valuable resource for understanding eosinophil-associated cardiac disease.
- This model facilitates research into the complex interplay of factors causing eosinophilic myocarditis and heart disease.
Background:
Heart disease (HD) is the major cause of morbidity and mortality in patients with hypereosinophilic diseases. Due to a lack of adequate animal models, our understanding of the pathophysiology of eosinophil-mediated diseases with heart complications is limited. We have discovered a mouse mutant, now maintained on an A/J inbred background, that spontaneously develops hypereosinophilia in multiple organs. Cellular infiltration into the heart causes an eosinophilic myocarditis, with affected mice of the mutant line (i.e., A/JHD) demonstrating extensive myocardial damage and remodeling that leads to HD and premature death, usually by 15-weeks old.
Results:
Maintaining the A/JHD line for many generations established that the HD trait was heritable and implied the mode of inheritance was not too complex. Backcross and intercross populations generated from mating A/JHD males with females from four different inbred strains produced recombinant populations with highly variable rates of affected offspring, ranging from none in C57BL/6 J intercrosses, to a few mice with HD using 129S1/SvImJ intercrosses and C57BL/6 J backcrosses, but nearly 8% of intercrosses and > 17% of backcrosses from SJL/J related populations developed HD. Linkage analyses of these SJL/J derived recombinants identified three highly significant loci: a recessive locus mapping to distal chromosome 5 (LOD = 4.88; named Emhd1 for eosinophilic myocarditis to heart disease-1); and two dominant variants mapping to chromosome 17, one (Emhd2; LOD = 7.51) proximal to the major histocompatibility complex, and a second (Emhd3; LOD = 6.89) that includes the major histocompatibility region. Haplotype analysis identified the specific crossovers that defined the Emhd1 (2.65 Mb), Emhd2 (8.46 Mb) and Emhd3 (14.59 Mb) intervals.
Conclusions:
These results indicate the HD trait in this mutant mouse model of eosinophilic myocarditis is oligogenic with variable penetrance, due to multiple segregating variants and possibly additional genetic or nongenetic factors. The A/JHD mouse model represents a unique and valuable resource to understand the interplay of causal factors that underlie the pathology of this newly discovered eosinophil-associated disease with cardiac complications.
