title: Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.
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.
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zech
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nübling
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Castrop
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jochim
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Schulte
authors.affiliation: Paracelsus-Elena-Klinik, Kassel, Germany ; Neurochirurgische Klinik, Georg-August-Universität, Göttingen, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany ; Institut für Humangenetik, Technische Universität München, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Laboratoire Gillet-Mérieux, CBPE, Hospices Civils de Lyon, Lyon, France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: Laboratoire Gillet-Mérieux, CBPE, Hospices Civils de Lyon, Lyon, France ; UF de Neurogénétique Moléculaire, CBPE, Hospices Civils de Lyon, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.affiliation: Klinik für Psychiatrie und Psychotherapie, Universität Regensburg, Regensburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Klünemann
authors.affiliation: Paracelsus-Elena-Klinik, Kassel, Germany ; Neurochirurgische Klinik, Georg-August-Universität, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Diehl-Schmid
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany ; Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, United Kingdom ; West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Perneczky
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany ; Institut für Humangenetik, Technische Universität München, Munich, Germany ; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany ; Institut für Humangenetik, Technische Universität München, Munich, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haslinger
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany ; Institut für Humangenetik, Technische Universität München, Munich, Germany ; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany ; Department of Neurology and Neurological Sciences and Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D013494:Supranuclear Palsy, Progressive / Q000235:genetics; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins