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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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68134 | GEO | 2015/05/19

SECONDARY ACCESSION(S): PRJNA284400

REPOSITORIES: GEO

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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

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

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

A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders

Project description:Human peroxisome biogenesis disorders are lethal genetic disease in which abnormal peroxisome assembly compromises overall peroxisome and cellular function. Peroxisomes are ubiquitous membrane-bound organelles involved in several important biochemical processes, notably lipid metabolism and the use of reactive oxygen species for detoxification. Using cultured cells, we systematically characterized the peroxisome assembly phenotypes associated with dsRNA-mediated knockdown of 14 predicted Drosophila homologs of PEX genes (encoding peroxins; required for peroxisome assembly and linked to peroxisome biogenesis disorders), and confirmed that at least 13 of them are required for normal peroxisome assembly. We also demonstrate the relevance of Drosophila as a genetic model for the early developmental defects associated with the human peroxisome biogenesis disorders. Mutation of the PEX1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form of the disease, Zellweger syndrome. Inherited mutations in Drosophila Pex1 correlate with reproducible defects during early development. Notably, Pex1 mutant larvae exhibit abnormalities that are analogous to those exhibited by Zellweger syndrome patients, including developmental delay, poor feeding, severe structural abnormalities in the peripheral and central nervous systems, and early death. Finally, microarray analysis defined clusters of genes whose expression varied significantly between wild-type and mutant larvae, implicating peroxisomal function in neuronal development, innate immunity, lipid and protein metabolism, gamete formation, and meiosis. Expression profiles were analyzed in triplicate from whole larvae of wild-type and pex1 homozygous mutant Drosophila.

2011-07-02 | E-GEOD-30362 | biostudies-arrayexpress

A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders

2011-07-02 | GSE30362 | GEO

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

The biochemical basis of mitochondrial dysfunction in 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.

2021-06-13 | GSE159869 | 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

Gene expression profiles of hepatocyte-like cells derived from induced pluripotent stem cells (iPSCs) from donors with the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD) and healthy controls

2015-05-21 | GSE69066 | 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

Project description:Skin fibroblasts from individuals with PBD-ZSD, a rare autosomal recessive disorder caused by peroxisome assembly defects, show defects in lipid metabolism that provide the basis for clinical diagnostic tests, but are not among the cell types most affected by disease. To explore phenotypes of more clinically relevant cell types, skin fibroblasts from PBD-ZSD patients and healthy controls were reprogrammed into iPS cells with all the hallmark properties of pluripotency. Subsequently, iPSCs were differentiated into ASGPR-positive hepatocyte-like cells that were subject to flow cytometry and subject to gene expression profiling. We report the gene expression profiles of hepatocyte-like cells derived from iPSCs that were themselves derived from skin fibroblasts from PBD-ZSD patient donors and healthy controls. The overall goal was to evaluate gene expression biomarkers of hepatocyte-like cells derived from PBD-ZSD patients and healthy controls. Dermal fibroblast cultures from 2 PBD-ZSD patients and 1 healthy control were reprogrammed into iPSCs by transfection with retroviruses designed to express the human OCT4, SOX2, KLF4 and c-MYC cDNA (see GEO entry GSE43996). Hepatic cell lineages were derived following the protocol of Duan (Duan Y, Catana A, Meng Y, Yamamoto N, He S, Gupta S et al. Stem Cells. 2007;25:3058-68; Duan Y, Ma X, Zou W, Wang C, Bahbahan IS, Ahuja TP et al. Stem Cells. 2010;28:674-86) with modifications. Total RNA samples from flow-sorted ASGPR-positive candidate hepatocyte-like cells obtained from healthy (control1) and PBD-ZSD patient (PBD_PEX1ms1 and PBD_PEX1fs1) donors were processed and analyzed on Affymetrix Human Genome 133A 2.0 microarrays.

2015-05-21 | E-GEOD-69066 | biostudies-arrayexpress

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