Lrrk2 in the limelight!

The past decade has seen an increasing proportion of patients with parkinsonism attributed to genetic causes.¹ Two genes, leucine-rich repeat kinase 2 (LRRK2; lrrk2) and α-synuclein, have been linked to dominant, late-onset Lewy body Parkinson disease (PD), whereas three genes, including parkin, PINK1, and DJ-1, have been linked to recessive early onset parkinsonism. Ironically, pedigree-based linkage analysis has proven informative in a disorder which is still largely considered sporadic. Within linked loci, polymorphic genetic variants have been reliably implicated in the risk of developing idiopathic PD. Other association studies, genetic or otherwise, have yet to prove as directive in the search for disease-modifying targets.¹

To date, lrrk2 G2019S and G2385R substitutions are the most frequently identified in PD. lrrk2 G2019S identified in white patients in the United States, Europe, the Middle East, and North Africa has negligible frequency in unrelated control subjects and in Asia.¹ Lrrk2 G2019S probably originates in Berber-Arabs where it accounts for disease in 30% of idiopathic PD² (unpublished observations). In contrast, lrrk2 G2385R is found in 8% of Asian patients and at 4% in control subjects in Japan, Singapore, and Taiwan (and presumably the Chinese mainland), but has negligible frequency in other ethnicities. …