Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders

PLoS One. 2013 Dec 30;8(12):e82879. doi: 10.1371/journal.pone.0082879. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aging / genetics
  • Carrier Proteins / genetics
  • Female
  • Frontotemporal Lobar Degeneration / genetics
  • Genetic Association Studies
  • Genetic Variation
  • Glycoproteins / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Glycoproteins / genetics
  • Neurodegenerative Diseases / genetics
  • Niemann-Pick C1 Protein
  • Niemann-Pick Diseases / genetics*
  • Parkinson Disease / genetics
  • Supranuclear Palsy, Progressive / genetics
  • Vesicular Transport Proteins

Substances

  • Carrier Proteins
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • NPC2 protein, human
  • Niemann-Pick C1 Protein
  • Vesicular Transport Proteins

Grants and funding

Recruitment and analysis of 94 patients with progressive supranuclear palsy was funded by Actelion Pharmaceuticals Ltd (www.actelion.com). The remaining study as well as the recruitment of patients with Parkinson's disease and frontotemporal lobar degeneration was funded by in-house institutional funding from Technische Universität München and Helmholtz Zentrum München, Munich, Germany. Controls belong to the KORA research platform (KORA, Cooperative Research in the Region of Augsburg), which was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.