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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

ABSTRACT: SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

PROVIDER: PRJNA718869 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11809821_1.fastq.gz	Fastqsanger.gz
	SRR11809821_2.fastq.gz	Fastqsanger.gz
	SRR11809822_1.fastq.gz	Fastqsanger.gz
	SRR11809822_2.fastq.gz	Fastqsanger.gz
	SRR11809823_1.fastq.gz	Fastqsanger.gz

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Molecular signature of Schinzel-Giedion syndrome in human neural progenitors

Project description:Schinzel-Giedion syndrome (SGS) is a developmental syndrome, due to the accumulation of SETBP1 protein, which is fatal in early infancy. SGS has a multi-organ involvement with severe and persistent intellectual and physical problems. We produced a human SGS model that outlines disease-relevant phenotypes using patient-derived induced pluripotent stem cells and isogenic controls. Whole transcriptome profiling describes cancer-like alterations in SGS neural progenitors including deregulation of oncogenes and suppressors and enhanced proliferation. These findings demonstrated how SGS post-natal pathological traits mayhave developmental origin in the failure of controlling cell identity and homeostasis due to SETBP1 protein accumulation.

2021-06-03 | GSE150810 | GEO

Gene expression profile of antisense oligonucleotide-treated Neural Progenitors from controls and Schinzel-Giedion Syndrome cases

Project description:Schinzel-Giedion Syndrome (SGS) is a severe multisystemic disorder caused by germline heterozygous missense mutations in a mutational hotspot found in SETBP1. Hotspot mutations affect the degron region of SETBP1, leading to an increase in SETBP1 protein levels. SGS has a range of neurological symptoms, including severe intellectual disability, frequent seizures, hydrocephalus, distorted neuronal layering, and delayed myelination, leading to early death in children. To investigate the gene expression change induced by a gapmer antisense oligonucleotide designed for treatment of SGS, we performed transcriptome analysis of neural progenitor cells from SGS cases and controls treated with an ASO targetting the SETBP1 gene, Inotersen ASO, vehicle-treated cells and untreated cells.

2026-05-15 | GSE315664 | GEO

Cell-type-specific expression and regulation in cerebral cortex and kidney of atypical Schinzel Giedion Syndrome mice

Project description:Schinzel Giedion Syndrome (SGS) is an ultra rare progressive neurodegenerative disease affecting less than 100 inividuals worldwide. SGS is cuased by variants in SETBP1 gene. We used snRNA-seq of cerebral cortex and kidney tissues from mice carrying a heterozygous S858R variant in Setbp1 and constructed cell-type-specific gene regulatory networks to profile the impact of the point mutation on cell-type-specific expression and regulation of Setbp1 and its known targets in atypical SGS. Grant Number: 1U54oD030167 UAB Pilot Center for Precision Animal Modeling (C-PAM) Grantee: Brittany Lasseigne Grant Number: 5T32GM008111-35 UAB CMDB T32 Grantee: Jordan Whitlock

2023-10-16 | GSE237816 | GEO

Single cell profiling of the cerebral organoids derived from Schinzel-Giedion syndrome cells and isogenic controls

Project description:Schinzel-Giedion syndrome (SGS) is a developmental syndrome, due to SETBP1 gene mutations inducing the accumulation of the relative protein, which is fatal in early infancy. Here, we generated unpatterned cerebral organoids from both SGS iPSC line and isogenic control line (through CRISPR/Cas9 back correction). We showed that SEBP1 accumulation triggers the development of large and convoluted epithelial folds in SGS cerebral organoids. To thoroughly characterize the 3D organoids we used scRNAseq (10X platform) in which we evidences the presence of both neural progenitors and committed neural progenitors with aberrant gene signature in SGS organoids that possibly sustain the lateral increase of the neuroepithelium

2021-06-03 | GSE171263 | GEO

SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome.

Project description: Not available

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Molecular signature of Schinzel-Giedion syndrome in human neural progenitors

Project description:Molecular signature of Schinzel-Giedion syndrome in human neural progenitors

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SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder [fibroblast]

Project description:Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syndrome (SGS, via missense variants at a critical degron region) and SETBP1-haploinsufficiency disorder. However, due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron region (n=18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-haploinsufficiency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.

2025-09-08 | GSE301238 | GEO

SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

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

2021-06-03 | GSE171266 | GEO

SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder [induced neurons]

2025-09-08 | GSE301239 | GEO

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

Project description: Not available

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