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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery

ABSTRACT: Chronic infantile neurological cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here, we report the generation of NLRP3-mutant and non-mutant induced pluripotent stem cell (iPSC) lines from two CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1M-NM-2 secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1M-NM-2 secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism, and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. To characterize iPS and differentiated cells, RNA expression profiles were evaluated by microarray analysis.We analyzed iPC cells and macrophage from healthy volunteers and CINCA syndrome patients. Human ES cella and fibroblasts were used as control.

ORGANISM(S): Homo sapiens

SUBMITTER: Akira Watanabe

PROVIDER: E-GEOD-38626 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery

Project description:Chronic infantile neurological cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here, we report the generation of NLRP3-mutant and non-mutant induced pluripotent stem cell (iPSC) lines from two CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism, and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders.

2012-06-11 | GSE38626 | GEO

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Expression data from control and Smith-Lemli-Opitz syndrome patient-derived iPS cells - comparison of cholesterol deficient and cholesterol rich culture

Project description:7-dehydrocholesterol reductase catalyzes the reduction of 7-dehydrocholesterol to cholesterol. In Smith-Lemli-Opitz syndrome, mutations in DHCR7 prevents this conversion. We have found iPS cells derived from SLOS patients exhibit accelerated differentiation under cholesterol poor conditions. In this dataset, we include expression data obtained from comparision of a control iPS cell line (BJ) and a SLOS iPS cell line (A2). Cell line gene expression was compared in cholesterol rich conditions where the SLOS phenotype is suppressed. Cholesterol deficient culture of control and SLOS iPS cells demonstrated enhanced differentiation of SLOS cells over 7 days. These data are used to obtain 308 genes that are differentially expressed upon cholesterol deficient culture. time-course expression data obtained from control and SLOS patient iPS cells after transfer from cholesterol rich to cholesterol deficient culture. 48 total RNA samples were isolated and hybridized on Affymetrix arrays. We generated the following pairwise comparisons using Partek: BJ 0hr vs A2 0hr; BJ 2Day vs A2 2Day; BJ 3Day vs A2 3Day; BJ 4Day vs A2 4Day; BJ 5Day vs A2 5Day; BJ 7Day vs A2 7Day. Genes with an FDR≤10% and a fold-change ≥3 were identified as significantly different. We also performed pairwise comparison of BJ and A2 samples within each cell line between subsequent isolations (i.e. BJ 0hr vs BJ 2Day; A2 3Day vs A2 4Day; etc.)

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