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

ABSTRACT: We profiled RNA expression in human iPSC-derived cardiomyocytes from patients with LZTR1-associated Noonan syndrome

ORGANISM(S): Homo sapiens

PROVIDER: GSE145348 | GEO | 2020/08/25

REPOSITORIES: GEO

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

Project description:We profiled RNA expression in human iPSC-derived cardiomyocytes from patients with LZTR1-associated Noonan syndrome

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Intronic CRISPR repair in LZTR1-deficient iPSC-cardiomyocytes from Noonan syndrome patients reveals new treatment options

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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Project description:Genetic variants in LZTR1 are associated with the development of Noonan syndrome. Here, we analyzed the proteome of cultured cardiomyocytes derived from hiPSCs with a pathological homozygous LZTR1 variant L580P in comparison to heterozygous and homozygous CRISPR/Cas9-corrected iPSC lines.

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CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy

Project description:CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy

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RNA-seq analysis of target genes in Noonan syndrome model mice with cardiac hypertrophy

Project description:Leucine-zipper-like transcriptional regulator 1 (LZTR1) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in LZTR1 have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether LZTR1 regulates the proteostasis of the RAS subfamily molecules and activate MAPK signaling pathway in heart. To investigate the impact of the LZTR1 mutant on gene expression, we performed RNA-seq analyses using LVs.

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

Project description:CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy I

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

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

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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.

2020-08-25 | GSE145350 | GEO

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

Project description:Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality early in life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, by analysis of sarcomeric myosin conformational states, histopathology and gene expression in left ventricular myocardial tissue from NS-CM, HCM and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

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