Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update

Abstract

To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; alpha-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include approximately 82% simple mutations and approximately 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.

Figure 1

Representation of SNCA on genomic and transcript level. All three transcripts coding for the same protein SNCA are depicted (t1: NM 001146055.1 /t2: NM_000345.2/t3: NM_007308.2). On transcript level exons are colored alternately.

Figure 2

Representation of LRRK2 on genomic and transcript level and the functional domains of the LRRK2 protein. On transcript level exons are colored alternately (NM_198578.2). (LRR: leucine-rich repeat; Roc: Ras-of-complex protein; COR: C-terminal of Roc.)

Figure 3

Representation of PARK2 on genomic and transcript level and the functional domains of the parkin protein. On transcript level exons are colored alternately (NM_004562.2). (UBL: ubiquitin-like; IBR: in-between-ring.)

Figure 4

Representation of PINK1 on genomic and transcript level and the functional domains of the PINK1 protein. On transcript level exons are colored alternately (NM_032409.2). (TM: transmembranair.)

Figure 5

Representation of PARK7 on genomic and transcript level. On transcript level exons are colored alternately (NM_007262.4).