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

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE167787 | GEO | 2021/02/27

REPOSITORIES: GEO

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

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

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Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs

Project description:Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations of SHP2. Although diverse neurological manifestations are commonly diagnosed in NS patients, mechanisms on how the SHP2 mutation induces the neurodevelopmental defects remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs normally develop in appearance, single-cell transcriptomic analysis represented increment of EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, EN subpopulation co-expressing upper layer marker SATB2 and deep layer maker CTIP2 was enriched in NS-COs during the cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity account for the neurological manifestations of NS.

2023-04-24 | GSE213798 | 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.

2022-01-11 | GSE188238 | GEO

Shp2 knockdown and Noonan/LEOPARD mutant Shp2-induced gastrulation defects.

Project description: Not available

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

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

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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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Chemokines expression effect of depletion of Shp2 on Kupffer cells

Project description:To investigate the monocyte-associated chemokines and adhesion molecules of NPCs between WT and Shp2Δk mice.We established shp2f/f//Clec4f-Cre mice to deplete Shp2 of KC.

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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.

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

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