Figure 1. LRRK2 mutations and domains.

Many variants in LRRK2 have been reported; some are clearly pathogenic, some are clearly not pathogenic and many are unclear. The tests for pathogenicity are either segregation (blue box) within families or association with disease across populations (yellow box) and mutations that pass either of these tests are placed in an approximate relationship to the linear sequence of the protein. Some mutations, such as R1441H, are probably causal but segregation data is less clear and these are listed in the grey box. Finally, a large number of polymorphic variants have been reported that are not likely to be pathogenic (white box). For the sake of clarity, not all reported mutations are listed. Here, we show only non-synonymous amino-acid-changing variants that were found only in controls (Paisán-Ruíz et al., 2008) and thus are very unlikely to be related to disease. The ideogram in the lower part of the Figure shows LRRK2 in a linear arrangement with each of the proposed domains labelled, from N- to C-termini; ANK, ankyrin-like repeats; LRR, leucine-rich repeats; ROC, Ras of complex proteins, GTPase domain; COR, C-terminal of ROC domain; kinase; WD40, a β-propeller-like domain made up of WD40 repeats. It should be noted that the clearly pathogenic variants cluster around the central enzymatic region, whereas clearly polymorphic changes are distributed throughout the molecule.