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An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.

ABSTRACT: Niemann-Pick disease, type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in either NPC1 or NPC2, which encodes an intracellular cholesterol-binding protein in lysosome. Deficiency of either NPC1 or NPC2 protein results in malfunction of intracellular cholesterol trafficking and lysosomal accumulation of unesterified cholesterols. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a male patient that has a homozygous p.I1061T missense mutation in NPC1 using a non-integrating Sendai virus technique. This NPC1 iPSC line offers a useful resource for disease modeling and drug development.

SUBMITTER: Li R

PROVIDER: S-EPMC7218921 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.

Li Rong R Pradhan Manisha M Xu Miao M Roeder Amanda A Beers Jeanette J Zou Jizhong J Liu Chengyu C Porter Forbes D FD Zheng Wei W

Stem cell research 20200219

Niemann-Pick disease, type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in either NPC1 or NPC2, which encodes an intracellular cholesterol-binding protein in lysosome. Deficiency of either NPC1 or NPC2 protein results in malfunction of intracellular cholesterol trafficking and lysosomal accumulation of unesterified cholesterols. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a male patient that has a homozygous p.I1061T mis ...[more]

PMID: 32114296

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Project description:BackgroundNiemann-Pick type C1 disease (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. In this lysosomal storage disorder the intracellular transport and sequestration of several lipids like cholesterol is severely impaired, resulting in an accumulation of lipids in late endosomes and lysosomes. The neurological manifestation of the disease is caused by dysfunction and cell death in the central nervous system. Several animal models were used to analyze the impaired pathways. However, the underlying pathogenic mechanisms are still not completely understood and the genetic variability in humans cannot be reflected in these models. Therefore, a human model using patient-specific induced pluripotent stem cells provides a promising approach.MethodsWe reprogrammed human fibroblasts from a NPC1 patient and a healthy control by retroviral transduction with Oct4, Klf4, Sox2 and c-Myc. The obtained human induced pluripotent stem cells (hiPSCs) were characterized by immunocytochemical analyses. Neural progenitor cells were generated and patch clamp recordings were performed for a functional analysis of derived neuronal cells. Filipin stainings and the Amplex Red assay were used to demonstrate and quantify cholesterol accumulation.ResultsThe hiPSCs expressed different stem cell markers, e.g. Nanog, Tra-1-81 and SSEA4. Using the embryoid body assay, the cells were differentiated in cells of all three germ layers and induced teratoma in immunodeficient mice, demonstrating their pluripotency. In addition, neural progenitor cells were derived and differentiated into functional neuronal cells. Patch clamp recordings revealed voltage dependent channels, spontaneous action potentials and postsynaptic currents. The accumulation of cholesterol in different tissues is the main hallmark of NPC1. In this study we found an accumulation of cholesterol in fibroblasts of a NPC1 patient, derived hiPSCs, and neural progenitor cells, but not in cells derived from fibroblasts of a healthy individual. These findings were quantified by the Amplex Red assay, demonstrating a significantly elevated cholesterol level in cells derived from fibroblasts of a NPC1 patient.ConclusionsWe generated a neuronal model based on induced pluripotent stem cells derived from patient fibroblasts, providing a human in vitro model to study the pathogenic mechanisms of NPC1 disease.

Dataset Information

An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.

Publications

An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.

Similar Datasets

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