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Published on: October 11, 2011
Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants
Tatiana Flisikowska1, Björn Petersen2, Giulia Mearini3,4
1Chair of Reproductive Biotechnology, Technical University of Munich (TUM), Munich, Germany.
Insights
Researchers created pig models for severe hypertrophic cardiomyopathy (HCM) using gene editing. These models, with mutations in MYBPC3 or MYH7 genes, developed cardiac hypertrophy and were non-viable, highlighting pig sensitivity to sarcomeric gene defects.
Area of Science:
- Cardiovascular Genetics
- Animal Models
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease often caused by mutations in sarcomeric protein genes like MYBPC3 and MYH7.
- Neonatal HCM forms can lead to rapid heart failure and early death.
- Current treatments for adult HCM are limited, necessitating new therapeutic strategies and predictive animal models.
Purpose of the Study:
- To develop pig models of severe human hypertrophic cardiomyopathy (HCM) by introducing specific genetic mutations.
- To investigate the effects of MYBPC3 and MYH7 gene variants on cardiac development and viability in pigs.
- To establish a preclinical platform for evaluating novel HCM therapies.
Main Methods:
- Utilized CRISPR/Cas9 genome editing and cytosine-base editing in porcine fibroblasts.
- Employed somatic cell nuclear transfer to generate genetically modified piglets.
- Introduced bi-allelic truncating MYBPC3 mutations or heterozygous missense MYH7 variants.
Main Results:
- Engineered piglets with compound heterozygous MYBPC3 mutations exhibited low mutant protein levels and cardiac hypertrophy.
- Piglets with the MYH7 p.Arg453Cys variant displayed ventricular hypertrophy.
- All edited piglets were non-viable, with severe cardiac hypertrophy and death around birth.
Conclusions:
- Pigs are highly sensitive to mutations in sarcomeric genes MYBPC3 and MYH7, leading to severe cardiac hypertrophy and perinatal lethality.
- The generated pig models mimic severe human neonatal HCM, offering a valuable tool for research.
- These findings underscore the critical role of sarcomeric proteins in cardiac development and highlight the need for targeted therapies for HCM.
Abstract:
Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease caused by genetic variants in sarcomeric proteins, particularly in myosin binding protein C3 (MYBPC3) and myosin heavy chain 7 (MYH7). Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life. Although myosin inhibitors are now used to treat obstructive forms of adult HCM, there is still a need for novel therapeutic options and predictive animal models to assess them. Our aim was to model in pigs severe forms of human HCM carrying bi-allelic truncating MYBPC3 mutations or heterozygous missense MYH7 variants. Pigs were generated by CRISPR/Cas9 genome or cytosine-base editing in porcine fibroblasts combined with somatic cell nuclear transfer. Several pregnancies were established but piglets were non-viable. The MYBPC3-edited piglet exhibited a compound heterozygous mutation leading to a markedly low level of mutant MYBPC3 protein and cardiac hypertrophy, reflecting the situation in infants. The MYH7-edited piglets carried the heterozygous p.Arg453Cys variant and exhibited ventricular hypertrophy. In conclusion, MYBPC3 and MYH7 cloned piglets developed cardiac hypertrophy and died around birth, indicating that pigs are particularly sensitive to sarcomeric gene mutations.
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