Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S]
A central feature of Niemann-Pick Type C (NPC) disease is sequestration of cholesterol and glycosphingolipids in lysosomes. A large phenotypic variability, on both a clinical as well as a molecular level, challenges NPC diagnosis. For example, substantial difficulties in identifying or excluding NPC...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2011-04-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520409150 |
| _version_ | 1818934003664683008 |
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| author | Carolina Tängemo Dominik Weber Susanne Theiss Eugen Mengel Heiko Runz |
| author_facet | Carolina Tängemo Dominik Weber Susanne Theiss Eugen Mengel Heiko Runz |
| author_sort | Carolina Tängemo |
| collection | DOAJ |
| description | A central feature of Niemann-Pick Type C (NPC) disease is sequestration of cholesterol and glycosphingolipids in lysosomes. A large phenotypic variability, on both a clinical as well as a molecular level, challenges NPC diagnosis. For example, substantial difficulties in identifying or excluding NPC in a patient exist in cases with a “variant” biochemical phenotype, where cholesterol levels in cultured fibroblasts, the primary diagnostic indicator, are only moderately elevated. Here we apply quantitative microscopy as an accurate and objective diagnostic tool to measure cholesterol accumulation at the level of single cells. When employed to characterize cholesterol enrichment in fibroblasts from 20 NPC patients and 11 controls, considerable heterogeneity became evident both within the population of cells cultured from one individual as well as between samples from different probands. An obvious correlation between biochemical phenotype and clinical disease course was not apparent from our dataset. However, plasma levels of HDL-cholesterol (HDL-c) tended to be in the normal range in patients with a “variant” as opposed to a “classic” biochemical phenotype. Attenuated lysosomal cholesterol accumulation in “variant” cells was associated with detectable NPC1 protein and residual capability to upregulate expression of ABCA1 in response to LDL. Taken together, our approach opens perspectives not only to support diagnosis, but also to better characterize mechanisms impacting cholesterol accumulation in NPC patient-derived cells.—Tängemo, C., D. Weber, S. Theiss, E. Mengel, and H. Runz. Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage. |
| first_indexed | 2024-12-20T04:57:22Z |
| format | Article |
| id | doaj.art-885a862f188d4dd79d0be40f5fbce00d |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T04:57:22Z |
| publishDate | 2011-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-885a862f188d4dd79d0be40f5fbce00d2022-12-21T19:52:40ZengElsevierJournal of Lipid Research0022-22752011-04-01524813825Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S]Carolina Tängemo0Dominik Weber1Susanne Theiss2Eugen Mengel3Heiko Runz4Institute of Human Genetics, University of Heidelberg, Heidelberg, GermanyInstitute of Human Genetics, University of Heidelberg, Heidelberg, GermanyInstitute of Human Genetics, University of Heidelberg, Heidelberg, GermanyLysosomal Storage Disease Group, University Children's Clinic, Mainz, GermanyInstitute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Lysosomal Storage Disease Group, University Children's Clinic, Mainz, Germany; To whom correspondence should be addressed. Heiko.Runz@med.uni-heidelberg.deA central feature of Niemann-Pick Type C (NPC) disease is sequestration of cholesterol and glycosphingolipids in lysosomes. A large phenotypic variability, on both a clinical as well as a molecular level, challenges NPC diagnosis. For example, substantial difficulties in identifying or excluding NPC in a patient exist in cases with a “variant” biochemical phenotype, where cholesterol levels in cultured fibroblasts, the primary diagnostic indicator, are only moderately elevated. Here we apply quantitative microscopy as an accurate and objective diagnostic tool to measure cholesterol accumulation at the level of single cells. When employed to characterize cholesterol enrichment in fibroblasts from 20 NPC patients and 11 controls, considerable heterogeneity became evident both within the population of cells cultured from one individual as well as between samples from different probands. An obvious correlation between biochemical phenotype and clinical disease course was not apparent from our dataset. However, plasma levels of HDL-cholesterol (HDL-c) tended to be in the normal range in patients with a “variant” as opposed to a “classic” biochemical phenotype. Attenuated lysosomal cholesterol accumulation in “variant” cells was associated with detectable NPC1 protein and residual capability to upregulate expression of ABCA1 in response to LDL. Taken together, our approach opens perspectives not only to support diagnosis, but also to better characterize mechanisms impacting cholesterol accumulation in NPC patient-derived cells.—Tängemo, C., D. Weber, S. Theiss, E. Mengel, and H. Runz. Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage.http://www.sciencedirect.com/science/article/pii/S0022227520409150cellular variabilitygenotype-phenotype relationshipimage analysislipoproteinneurodegeneration |
| spellingShingle | Carolina Tängemo Dominik Weber Susanne Theiss Eugen Mengel Heiko Runz Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] Journal of Lipid Research cellular variability genotype-phenotype relationship image analysis lipoprotein neurodegeneration |
| title | Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] |
| title_full | Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] |
| title_fullStr | Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] |
| title_full_unstemmed | Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] |
| title_short | Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage[S] |
| title_sort | niemann pick type c disease characterizing lipid levels in patients with variant lysosomal cholesterol storage s |
| topic | cellular variability genotype-phenotype relationship image analysis lipoprotein neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520409150 |
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