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Pex1-G844D NMRI mouse model of mild Zellweger spectrum disorder: liver gene expression profiles

ABSTRACT: Pex1-G844D NMRI mouse model of mild Zellweger spectrum disorder: liver gene expression profiles

PROVIDER: PRJNA607508 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11111660_1.fastq.gz	Fastqsanger.gz
	SRR11111660_2.fastq.gz	Fastqsanger.gz
	SRR11111661_1.fastq.gz	Fastqsanger.gz
	SRR11111661_2.fastq.gz	Fastqsanger.gz
	SRR11111662_1.fastq.gz	Fastqsanger.gz

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Pex1-G844D NMRI mouse model of mild Zellweger spectrum disorder: liver gene expression profiles

Project description:Zellweger spectrum disorders (ZSD) are inborn metabolic diseases cause by genetic alterations in PEX genes leading to peroxisomal biogenesis disorder (PBD). Supportive care is standard since no validated treatment is able to modify the dismal natural history of the disease. Mouse models exist to study ZSD pathophysiology but they are limited by poor survival of the affected pups and breeding restrictions. To overcome these limitations, hypomorphic Pex1 p.G844D allele, equivalent to common mild human PEX1 p.G843D mutation, was backcrossed from C57BL/6N mouse to NMRI background. NMRI ZSD mouse breeding lead autosomal recessive Mendelian inheritance pattern with (median (min-max)) 10 (7-15) pups/mating compared to 4 (2-7) pups/mating in C57BL/6N background (p < 0.0001). We longitudinally phenotyped NMRI ZSD mice at 1, 2, 3 and 6 months of age to render this model suitable for future therapeutic interventions. NMRI ZSD mice exhibited growth retardation despite their higher daily energy intake. Mouse embryonic fibroblasts displayed classical PBD immunofluorescence pattern with peroxisomal mosaicism like milder ZSD patients skin fibroblasts. ZSD mice liver were enlarged and no liver lipid accumulation was detected. Yet, ZSD mouse plasma and liver showed very long-chain fatty acids, oxysterols and C27 bile acids intermediates elevation. Longitudinal study depicted trend to normalization for C26 and phytanic acid as it was shown for some ZSD patients reaching adulthood. ZSD mouse liver glycogen content was drastically reduced and liver RNA-Seq analysis confirmed glycogen metabolism genes downregulation. In conclusion, NMRI ZSD mouse model is suitable for ZSD liver-targeted therapies evaluation.

2020-02-20 | GSE145524 | GEO

Retinas from the Pex1-G844D mouse model of Zellweger spectrum disorder

Project description:Gene expression analysis of retinas from a mouse model of the mild form of Zellweger spectrum disorder (ZSD). Mice homozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive ZSD, develop phenotypes found in humans with a milder form of ZSD, including retinal degeneration and vision loss. Similar to humans, mice heterozygous for the hypomorphic Pex1-G844D allele do not display age-related retinal abnormalities. We conducted a comparative analysis of retinal gene expression profile from Pex1-G844D homozygous and heterozygous mice in order to investigate the pathomechanisms of vision loss in humans with mild forms of ZSD. Whole retinas were obtained from 4 mice homozygous and 4 mice heterozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive Zellweger spectrum disorder (ZSD). The former group of animals show abnormal age-related related retinal degeneration due to peroxisome assembly defect resulting from having two copies of the hypomorphic Pex1-G844D allele. The latter group of animals display no evidence of abnormal age-related retinal degeneration due to the presence of one wild type copy of the Pex1 gene. The overall goal was to identify differentially expressed genes between mice homozygous and heterozygous for the hypomorphic Pex1-G844D allele that are informative of the pathomechanisms of age-related retinal degeneration in the former group.

2013-12-15 | E-GEOD-52348 | biostudies-arrayexpress

Retinas from the Pex1-G844D mouse model of Zellweger spectrum disorder

2013-12-15 | GSE52348 | GEO

The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Project description:The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

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Gene expression profiles of fibroblasts and induced pluripotent stem cells (iPSCs) from individuals with Zellweger spectrum disorder (ZSD), a class of peroxisome biogenesis disorder, and healthy controls

2015-03-24 | GSE43996 | GEO

The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Project description:We identified that peroxins were still expressed in Zellweger Spectrum Disorder (ZSD) and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. In this complexome analysis we detected several peroxins in the mitochondrial fraction in the absence of functional peroxisomes and that this accumulation is exacerbated by the loss of the mitochondrial extractase Msp1. In addition, we observed that specific peroxisomal matrix proteins localize to the mitochondria, which suggest that a functional peroxisomal docking and import complex assembles on the mitochondria in the absence of peroxisomes.

2021-06-25 | PXD024625 | Pride

DNA methylation profiles of fibroblasts and induced pluripotent stem cells (iPSCs) from individuals with Zellweger spectrum disorder (ZSD), a class of peroxisome biogenesis disorder, and healthy controls

2015-05-19 | GSE68134 | GEO

The biochemical basis of mitochondrial dysfunctionin Zellweger Spectrum Disorder

Project description:Peroxisomal Biogenesis Disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger Spectrum Disorder(ZSD)—is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.

2021-05-10 | PXD025595 | Pride

Project description:Zellweger spectrum disorder (PBD-ZSD) is a disease continuum caused by mutations in a subset of PEX genes required for normal peroxisome assembly and function. Their clinical manifestations highlight the importance of peroxisomes in the development and functions of the central nervous system, liver, and other organs. Although much is known about peroxisome assembly and activities, the underlying bases for the cell-type specificity of disease are not fully elucidated. We reprogrammed skin fibroblasts from PBD-ZSD patients into induced pluripotent stem cells (iPSCs) and report their DNA methylation profiles as well as those of matching healthy controls. Dermal fibroblast cultures from 6 PBD-ZSD patient and 3 healthy control donors were reprogrammed into iPSCs by transfection with retroviruses designed to express the human OCT4, SOX2, KLF4 and c-MYC genes. Fibroblasts and iPSCs were cultured in 1:1 ratio of DMEM:F12 medium supplemented with 20% KSR at 37°C with 5% CO2 until confluence for RNA extraction. The overall goal was to confirm the epigenetic reprogramming of iPSCs and identify loci that are differentially methylated between PBD-ZSD patient and healthy control cells in order to gain insights into the pathomechanisms of disease.

2015-05-19 | E-GEOD-68134 | biostudies-arrayexpress

Transcriptional organization of autism spectrum disorder

Project description:Transcriptional organization of autism spectrum disorder

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