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CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy II

ABSTRACT: CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy II

PROVIDER: PRJNA606802 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11091663.fastq.gz	Fastqsanger.gz
	SRR11091664.fastq.gz	Fastqsanger.gz
	SRR11091665.fastq.gz	Fastqsanger.gz
	SRR11091666.fastq.gz	Fastqsanger.gz
	SRR11091667.fastq.gz	Fastqsanger.gz

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CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy

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CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy II

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Project description:Noonan syndrome (NS) is a multisystemic developmental disorder characterized by its clinical variability with common symptoms such as typical facial dysmorphism, short stature, developmental delay and intellectual disability as well as congenital heart disease. The disease is causally linked to gain-of-function mutations in a number of genes leading to an increased signal transduction along the RAS-MAP kinase (MAPK) signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. In this study, we present a family with two siblings displaying an autosomal recessive form of NS with severe hypertrophic cardiomyopathy caused by biallelic mutations within leucine zipper like transcription regulator 1 (LZTR1). Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings recapitulated the hypertrophic phenotype and uncovered a causal link between LZTR1 dysfunction, RAS accumulation, RAS-MAPK signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Intronic CRISPR repair in the patients’ iPSCs normalized RAS-MAPK signaling activity and cellular hypertrophy paving the way for personalized medical treatment.

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CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy

Project description:This SuperSeries is composed of the SubSeries listed below.

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Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

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Project description:Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1 L613V/+ knock-in mice. Here, using inducible Raf1 L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1 L613V enhances Ca 2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1 L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1 L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine hierarchy (TNFα->IL6) from Raf1 L613V -expressing ECs that drives cardiomyocyte hypertrophy in vitro. Furthermore, post-natal TNFα inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo. We conclude that NS cardiomyopathy involves cardiomyocytes, ECs, and fibroblasts, TNFα/IL6 signaling components represent potential therapeutic targets, and abnormal EC signaling might contribute to other forms of LVH.

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