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Protein Profiling of human iPSC-derived cardiomyocytes with a recessive LZTR1 variant in comparison to wild type cells

ABSTRACT: 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 two wild type iPSC lines.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Regular Cardiac Myocyte

DISEASE(S): Noonan Syndrome

SUBMITTER: Elke Hammer

LAB HEAD: Elke Hammer

PROVIDER: PXD038425 | Pride | 2024-07-02

REPOSITORIES: Pride

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			Action	DRS
	20201026_Exp_AW_DZHKe_18_WT_04.raw	Raw
	20201026_Exp_AW_DZHKe_19_WT118_01.raw	Raw
	20201026_Exp_AW_DZHKe_1_HoCMx114_17.raw	Raw
	20201026_Exp_AW_DZHKe_20_WT_02.raw	Raw
	20201026_Exp_AW_DZHKe_21_WT_03.raw	Raw

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Similar Datasets

Protein Profiling of human iPSC-derived cardiomyocytes with a recessive LZTR1 variant in comparison to CRISPR/Cas9-corrected cells

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.

2024-07-02 | PXD038417 | Pride

Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

Project description:Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes, have been recently associated with Noonan syndrome and familial Schwannomatosis. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. In the present dataset we screened for changes in the ubiquitin landscape induced by LZTR1 loss of function by mass spectrometry-based proteomics and identified RAS proteins as substrates of the LZTR1/CUL3 complex. In follow-up experiments we showed that LZTR1/CUL3 inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. Together, our results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to human disease.

2018-11-07 | PXD007035 | Pride

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

Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

Project description:Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes1, have been recently associated with Noonan syndrome2,3 and familial Schwannomatosis4-6. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. We screened for LZTR1 substrates by trapping LZTR1 complexes from intact mammalian cells. In parallel, we analysed changes in the ubiquitin landscape induced by LZTR1 loss of function. RAS proteins emerged as substrates of the LZTR1/CUL3 complex, which inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. These results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to a human disease.

2018-11-04 | PXD007049 | Pride

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

2020-08-25 | GSE145348 | GEO

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

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.

2024-10-23 | GSE254067 | GEO

Quantitative Analysis of Wild Type and Lztr1 +/- Transcriptomes in MEFs (murine embryonic fibroblasts)

Project description:The goals of this study are to compare MEFs transcriptome profiling (RNA-seq) from Lztr1 +/+ and +/- mice. MEFs were isolated from E12,5 embryos,

2018-11-29 | GSE123044 | 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

Integrative Molecular and Clinical Profiling of Acral Melanoma Identifies LZTR1 as a Key Tumor Promoter and Therapeutic Target

Project description:Acral melanoma, the most common melanoma subtype among non-Caucasian individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we performed integrative genomic and clinical profiling of acral melanomas from a cohort of 104 patients treated in North America or China. We found that recurrent, late-arising amplifications of cytoband chr22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 – a known tumor suppressor in other cancers – is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines caused apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiated processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and increased levels of MAPK and SRC activities. Our results provide new insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target. Keywords: Expression profiling by high throughput sequencing

2021-12-14 | GSE190113 | GEO

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