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

Tatiana Flisikowska , Björn Petersen , Giulia Mearini , Daniela Huber , Mayuko Kurome , Melanie Stoff , Saskia Schlossarek , Andrea Lucas-Hahn , Eckhard Wolf , Judith Montag , Angelika Schnieke , Lucie Carrier
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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.
携带肌瘤致病变异的肥厚性心肌病猪模型的围产期死亡
肥厚性心肌病(HCM)是一种常染色体显性疾病,由肌凝蛋白,特别是肌凝蛋白结合蛋白C3 (MYBPC3)和肌凝蛋白重链7 (MYH7)基因变异引起。鲜为人知的是,新生儿形式的HCM会迅速演变为收缩期心力衰竭,并在出生后一年内死亡。尽管肌球蛋白抑制剂现在被用于治疗阻塞性成人HCM,但仍需要新的治疗选择和预测性动物模型来评估它们。我们的目的是在猪身上模拟携带双等位基因截断MYBPC3突变或杂合错义MYH7变异的严重形式的人类HCM。通过CRISPR/Cas9基因组或胞嘧啶碱基编辑在猪成纤维细胞中结合体细胞核移植产生猪。有几只小猪怀孕,但仔猪不能存活。经过MYBPC3编辑的仔猪表现出一种复合杂合突变,导致MYBPC3突变蛋白水平显著降低和心脏肥厚,反映了婴儿的情况。经过myh7编辑的仔猪携带杂合子p.a g453cys变体,并表现出心室肥厚。综上所述,MYBPC3和MYH7克隆仔猪出现心肌肥厚并在出生前后死亡,表明猪对肉瘤基因突变特别敏感。
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来源期刊
Journal of molecular and cellular cardiology plus
Journal of molecular and cellular cardiology plus Cardiology and Cardiovascular Medicine
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