Clinical features of LRRK2 parkinsonism

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were initially identified in large families with autosomal dominant Parkinson disease (PD). These mutations (p.R1441C, p.R1441G, p.Y1699C and p.I2020T) revealed that genetic mutations could cause clinically typical, late-onset PD. Subsequently, the p.G2019S mutation was found to be a frequent cause of both autosomal dominant and "sporadic" PD, particularly in populations in North Africa or the Middle East. Two Lrrk2 protein substitutions (p.R1628P and p.G2385R) have since been associated with susceptibility to PD in Asian populations. More than a hundred variants have been identified in the LRRK2 gene, but pathogenicity is most convincing for the p.R1441H substitution. The role in PD remains unknown for other variants because segregation with disease has not been shown. Screening these variants in very large patient-control series may help clarify their role in PD. Lrrk2 is a large, multidomain protein with pathogenic mutations occurring in several functional domains. Cell biological experiments have shown that the p.G2019S mutation increase kinase activity. This is consistent with the observation that homozygous p.G2019S carriers do not have earlier disease onset or more severe disease compared with heterozygous carries. It is now necessary to identify the regulators and substrates of Lrrk2 in order to understand the effect of each LRRK2 mutation. The identification of a large number of presymptomatic LRRK2 mutation carriers provides a unique possibility for future studies on neuroprotection. However, more insight into the basic function of Lrrk2 is needed in order to exploit this potential for translational research.