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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

2020-12-01 | GSE145349 | GEO

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.

2020-08-25 | PXD017530 | Pride

CRISPR repair in a preclinical model of Noonan syndrome associated cardiomyopathy

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

| PRJNA606799 | ENA

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

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 I

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

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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.

2022-01-11 | GSE188238 | GEO

Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking

Project description:Mutations in LZTR1, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, are associated with glioma, hepatocarcinoma, paediatric cancers, Schwannomatosis, and Noonan syndrome (NS). NS is a poorly understood and complex disease. The variety of NS phenotypes makes it challenging to elucidate the molecular mechanisms by which mutations in LZTR1 drive human disease. Using an Lztr1 knockout model, we assessed the effect of Lztr1 loss on endothelial function. Moreover, the molecular alterations mediated by Lztr1 loss were evaluated by mass-spectrometry (MS)-based ubiquitome and proteome analysis. These analyses demonstrated that Lztr1 loss affects vesicular trafficking. We identified the ESCRT III member CHMP1B as a substrate for the LZTR1/CUL3 ubiquitin complex and could show that disease-related LZTR1 mutations abolish the interaction with CHMP1B. LZTR1-mediated ubiquitination of CHMP1B facilitates its interaction with IST1 that affects the dynamics of fusion and fission of endosomal vesicles. Dysregulation of vesicular trafficking triggered by Lztr1 loss leads to up-regulation of VEGF signaling due to endosomal accumulation and activation of VEGFR2. This novel molecular mechanism provides a fundamental explanation for the role of LZTR1 in endothelial function and justify the use of anti-VEGF therapies for the treatment of NS patients.

2020-10-14 | PXD011926 | Pride

Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome

Project description:Hematopoietic stem and progenitor cells derived from a zebrafish model of Noonan syndrome, carrying a patient-associated Shp2-D61G mutation, display an expansion of monocyte/macrophage progenitors with an inflammatory gene expression signature.

2021-02-27 | GSE167787 | GEO

Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome

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.

2017-05-22 | GSE95739 | GEO

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