Abstract
To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include ∼82% simple mutations and ∼18% copy number variations. Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses. Here we present an update of all mutations published to date in the literature, systematically organized in a novel mutation database (http://www.molgen.ua.ac.be/PDmutDB). In addition, we address the biological relevance of putative pathogenic mutations. This review emphasizes the need for comprehensive genetic screening of Parkinson patients followed by an insightful study of the functional relevance of observed genetic variants. Moreover, while capturing existing data from the literature it became apparent that several of the five Parkinson genes were also contributing to the genetic etiology of other Lewy Body Diseases and Parkinson-plus syndromes, indicating that mutation screening is recommendable in these patient groups. Hum Mutat 31:763–780, 2010. © 2010 Wiley-Liss, Inc.
Highlights
Parkinson disease (PD) is the second most common progressive neurodegenerative brain disorder
Follow-up genetic studies are inconsistent for some of these genes or conclusive data are still pending, ample evidence for a causal association was obtained for PD with five genes, that is, a-synuclein (SNCA; MIM] 163890), parkin (PARK2; MIM] 602544), PTEN-induced putative kinase 1 (PINK1; MIM] 608309), DJ-1 (PARK7; MIM] 602533), and Leucine-rich repeat kinase 2 (LRRK2; MIM] 609007)
During the last 2 decades molecular genetic research has lead to the identification of five important PD genes bearing approximately 500 different DNA variants
Summary
Parkinson disease (PD) is the second most common progressive neurodegenerative brain disorder. Several of these dosage studies attempted to delineate the boundaries of the multiplicated genomic region identified in families or shared between unrelated carriers. (%) Number of (possible) pathogenic mutations for this gene/total number of (possible) pathogenic mutations
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