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Schulte, E.C. ; Ellwanger, D.C.* ; Dihanich, S.* ; Manzoni, C.* ; Stangl, K.* ; Schormair, B. ; Graf, E. ; Eck, S. ; Mollenhauer, B.* ; Haubenberger, D.* ; Pirker, W.* ; * ; Brücke, T.* ; Lichtner, P. ; Peters, A. ; Gieger, C. ; Trenkwalder, C.* ; Mewes, H.-W.* ; Meitinger, T. ; Lewis, P.A.* ; Klünemann, H.H.* ; Winkelmann, J.

Rare variants in LRRK1 and Parkinson's disease.

Neurogenetics 15, 49-57 (2014)
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Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Parkinsons's disease; LRRK1; EEF1D; Exome sequencing; Repeat Kinase Lrrk1; Endosomal Trafficking; Alpha-synuclein; Mutations; Gene; Heterodimerization; Vps35; Risk
Language english
Publication Year 2014
Prepublished in Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 1364-6745
e-ISSN 1364-6753
Journal Neurogenetics
Quellenangaben Volume: 15, Issue: 1, Pages: 49-57 Article Number: , Supplement: ,
Publisher Springer
Publishing Place New York
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30505 - New Technologies for Biomedical Discoveries
30202 - Environmental Health
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-500700-001
G-504100-001
G-503700-001
G-504000-001
G-504000-005
PubMed ID 24241507
DOI 10.1007/s10048-013-0383-8
WOS ID WOS:000333707900007
Scopus ID 84897954643
Erfassungsdatum 2013-11-22
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