Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease

Niemann–Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the <i>NPC1</i> gene. Patients display a wide spectrum on the clinical as well as on the molecular level, wherein a so-called “variant” biochemical phenotype can be observ...

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Autores principales:	Christin Völkner, Maik Liedtke, Robert Untucht, Andreas Hermann, Moritz J. Frech
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	NP-C1 induced pluripotent stem cells iPSCs filipin cholesterol NPC1 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/b7de588aa0844736a49b3bfb7d12ad88
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spelling	oai:doaj.org-article:b7de588aa0844736a49b3bfb7d12ad882021-11-25T17:54:06ZPatient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease10.3390/ijms2222121841422-00671661-6596https://doaj.org/article/b7de588aa0844736a49b3bfb7d12ad882021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12184https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Niemann–Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the <i>NPC1</i> gene. Patients display a wide spectrum on the clinical as well as on the molecular level, wherein a so-called “variant” biochemical phenotype can be observed. Here, we report an in vitro analysis of fibroblasts obtained from an NP-C1 patient carrying the undescribed compound heterozygous mutation p.V1023Sfs15/p.G992R. Since NP-C1 is a neurovisceral disease and the patient suffers from severe neurological as well as hepatic symptoms, we extended our study to neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells. We detected slightly increased intracellular cholesterol levels compared to the control cell line in fibroblasts, neural differentiated and hepatocyte-like cells, suggesting a “variant” biochemical phenotype. Furthermore, the total NPC1 protein, as well as post-ER glycoforms of the NPC1 protein, tended to be reduced. In addition, colocalization analysis revealed a mild reduction of the NPC1 protein in the lysosomes. The patient was diagnosed with NP-C1 at the age of 34 years, after an initial misdiagnosis of schizophrenia. After years of mild and unspecific symptoms, such as difficulties in coordination and concentration, symptoms progressed and the patient finally presented with ataxia, dysarthria, dysphagia, vertical supranuclear gaze palsy, and hepatosplenomegaly. Genetic testing finally pointed towards an NP-C1 diagnosis, revealing the so-far undescribed compound heterozygous mutation p.V1023Sfs*15/p.G992R in the <i>NPC1</i> gene. In light of these findings, this case provides support for the p.G992R mutation being causative for a “variant” biochemical phenotype leading to an adult-onset type of NP-C1 disease.Christin VölknerMaik LiedtkeRobert UntuchtAndreas HermannMoritz J. FrechMDPI AGarticleNP-C1induced pluripotent stem cellsiPSCsfilipincholesterolNPC1Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12184, p 12184 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NP-C1 induced pluripotent stem cells iPSCs filipin cholesterol NPC1 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	NP-C1 induced pluripotent stem cells iPSCs filipin cholesterol NPC1 Biology (General) QH301-705.5 Chemistry QD1-999 Christin Völkner Maik Liedtke Robert Untucht Andreas Hermann Moritz J. Frech Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
description	Niemann–Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the <i>NPC1</i> gene. Patients display a wide spectrum on the clinical as well as on the molecular level, wherein a so-called “variant” biochemical phenotype can be observed. Here, we report an in vitro analysis of fibroblasts obtained from an NP-C1 patient carrying the undescribed compound heterozygous mutation p.V1023Sfs15/p.G992R. Since NP-C1 is a neurovisceral disease and the patient suffers from severe neurological as well as hepatic symptoms, we extended our study to neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells. We detected slightly increased intracellular cholesterol levels compared to the control cell line in fibroblasts, neural differentiated and hepatocyte-like cells, suggesting a “variant” biochemical phenotype. Furthermore, the total NPC1 protein, as well as post-ER glycoforms of the NPC1 protein, tended to be reduced. In addition, colocalization analysis revealed a mild reduction of the NPC1 protein in the lysosomes. The patient was diagnosed with NP-C1 at the age of 34 years, after an initial misdiagnosis of schizophrenia. After years of mild and unspecific symptoms, such as difficulties in coordination and concentration, symptoms progressed and the patient finally presented with ataxia, dysarthria, dysphagia, vertical supranuclear gaze palsy, and hepatosplenomegaly. Genetic testing finally pointed towards an NP-C1 diagnosis, revealing the so-far undescribed compound heterozygous mutation p.V1023Sfs15/p.G992R in the <i>NPC1</i> gene. In light of these findings, this case provides support for the p.G992R mutation being causative for a “variant” biochemical phenotype leading to an adult-onset type of NP-C1 disease.
format	article
author	Christin Völkner Maik Liedtke Robert Untucht Andreas Hermann Moritz J. Frech
author_facet	Christin Völkner Maik Liedtke Robert Untucht Andreas Hermann Moritz J. Frech
author_sort	Christin Völkner
title	Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
title_short	Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
title_full	Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
title_fullStr	Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
title_full_unstemmed	Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease
title_sort	patient-specific ipsc-derived neural differentiated and hepatocyte-like cells, carrying the compound heterozygous mutation p.v1023sfs*15/p.g992r, present the “variant” biochemical phenotype of niemann-pick type c1 disease
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b7de588aa0844736a49b3bfb7d12ad88
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Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the “Variant” Biochemical Phenotype of Niemann-Pick Type C1 Disease

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