In affected members of a family with autosomal dominant Parkinson disease (PARK8; 607060) originally reported by Wszolek et al. (1995), Zimprich et al. (2004) identified a heterozygous 4321C-T transition in the LRRK2 gene, resulting in an arg1441-to-cys (R1441C) substitution in the ROC (GTPase) domain. Affected members of another unrelated family also had the R1441C mutation. The mutation was not identified in more than 1,000 control individuals or 300 patients with sporadic PD.
West et al. (2005) determined that the R1441C mutation, which lies within the GTPase domain of LRRK2, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that R1441C appeared to enhance protein kinase activity.
Tong et al. (2009) found that mutant knockin mice with expression of normal levels of the R1441C mutant protein appeared grossly normal and did not show any evidence of dopaminergic degeneration up to 2 years of age. However, knockin mice showed impaired augmentation of locomotor activity in response to amphetamine compared to wildtype, suggesting a defect in drug-induced dopamine release. Adrenal chromaffin cells derived from mutant mice showed a significant reduction in stimulus-induced catecholamine release compared to controls. Mutant mice also showed impaired dopamine D2 receptor (DRD2; 126450)-mediated functions, such as reduced response to the locomotor inhibitory effect of a DRD2 agonist and decreased cellular sensitivity to suppression by DRD2 agonists. Tong et al. (2009) suggested that these changes may represent pathogenic precursors to dopaminergic degeneration.
