The genetics of Parkinson disease

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder. In most instances, PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated. The prevalence, incidence, clinical manifestations, and genetic components of PD are discussed in this review.

Figure 1

SNCA (PARK1/PARK4) gene and protein structure. All exons and functional domains are shown. All 3 point mutations identified to date are also shown. ATG indicates the beginning of the coding region (gray); Ex, exon; aa, amino acid.

Figure 2

LRRK2 (PARK8) gene and protein structure. Established pathogenic mutations (boldface) and risk variants (gray) are shown. Variants specific to Asian populations are indicated by an asterisk. ARM indciates Armadillo region; ANK, Ankyrin repeat region; LRR, leucine-rich repeat domain; ROC, Ras of complex; COR, C terminal of Ras (GTPase);. MAPKKK, mitogen-activated protein kinase kinase kinase; Ex, exon; aa, amino acid.

Figure 3

PARK2 gene and protein structure. More than 100 mutations have been identified. Number of mutations in each exon is shown as reported in the PD mutation database http://grenada.lumc.nl/LOVD2/TPI/home.php?select_db=PARK2. Hot spots for parkin mutations are concentrated in exons 2 and 7, whereas hot spots for exon rearrangements occur in introns 2 through 4. ATG indicates the beginning of the coding region (gray); UBL, ubiquitin-like domain; Ex, exon; aa, amino acid.