Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.
Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are like...
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oai:doaj.org-article:1994152f2374473292db8c130bebc0322021-11-18T08:39:58ZNiemann-Pick C disease gene mutations and age-related neurodegenerative disorders.1932-620310.1371/journal.pone.0082879https://doaj.org/article/1994152f2374473292db8c130bebc0322013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24386122/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.Michael ZechGeorg NüblingFlorian CastropAngela JochimEva C SchulteBrit MollenhauerPeter LichtnerAnnette PetersChristian GiegerThorsten MarquardtMarie T VanierPhilippe LatourHans KlünemannClaudia TrenkwalderJanine Diehl-SchmidRobert PerneczkyThomas MeitingerKonrad OexleBernhard HaslingerStefan LorenzlJuliane WinkelmannPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e82879 (2013) |
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DOAJ |
| collection |
DOAJ |
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EN |
| topic |
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| spellingShingle |
Medicine R Science Q Michael Zech Georg Nübling Florian Castrop Angela Jochim Eva C Schulte Brit Mollenhauer Peter Lichtner Annette Peters Christian Gieger Thorsten Marquardt Marie T Vanier Philippe Latour Hans Klünemann Claudia Trenkwalder Janine Diehl-Schmid Robert Perneczky Thomas Meitinger Konrad Oexle Bernhard Haslinger Stefan Lorenzl Juliane Winkelmann Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| description |
Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted. |
| format |
article |
| author |
Michael Zech Georg Nübling Florian Castrop Angela Jochim Eva C Schulte Brit Mollenhauer Peter Lichtner Annette Peters Christian Gieger Thorsten Marquardt Marie T Vanier Philippe Latour Hans Klünemann Claudia Trenkwalder Janine Diehl-Schmid Robert Perneczky Thomas Meitinger Konrad Oexle Bernhard Haslinger Stefan Lorenzl Juliane Winkelmann |
| author_facet |
Michael Zech Georg Nübling Florian Castrop Angela Jochim Eva C Schulte Brit Mollenhauer Peter Lichtner Annette Peters Christian Gieger Thorsten Marquardt Marie T Vanier Philippe Latour Hans Klünemann Claudia Trenkwalder Janine Diehl-Schmid Robert Perneczky Thomas Meitinger Konrad Oexle Bernhard Haslinger Stefan Lorenzl Juliane Winkelmann |
| author_sort |
Michael Zech |
| title |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| title_short |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| title_full |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| title_fullStr |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| title_full_unstemmed |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. |
| title_sort |
niemann-pick c disease gene mutations and age-related neurodegenerative disorders. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/1994152f2374473292db8c130bebc032 |
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| _version_ |
1718421485982318592 |