Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants

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.

Keywords

• Base editing
• CRISPR/Cas9
• Gene editing
• Hypertrophic cardiomyopathy
• MYBPC3
• MYH7