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Rare variants in LRRK1 and Parkinson's disease

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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., Zimprich, A., Brücke, T., Lichtner, P., Peters, A., Gieger, C., Trenkwalder, C., Mewes, H.-W., Meitinger, T., Lewis, P. A., Klünemann, H. H. and Winkelmann, J. (2014) Rare variants in LRRK1 and Parkinson's disease. Neurogenetics, 15 (1). pp. 49-57. ISSN 1364-6745

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To link to this item DOI: 10.1007/s10048-013-0383-8

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Centre for Integrative Neuroscience and Neurodynamics (CINN)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:37259
Uncontrolled Keywords:Parkinson's disease LRRK1 EEF1D Exome sequencing
Publisher:Springer

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