Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant...

Parkinson's disease (PD) is a neurodegenerative disorder characterized by neurodegeneration, most notably of dopaminergic neurons in the substantia nigra. To date, six causative genes have been identified including LRRK2, whose mutations are the most frequent in autosomal dominant PD (Ad-PD). We conducted a comprehensive mutational analysis of LRRK2 in 30 Ad-PD (11 Japanese and 19 Caucasian) families employing a DNA microarray-based resequencing system and direct nucleotide sequence analysis, and identified 23 variants including two known mutations, p.G2019S and p.I1371V, in three Caucasian families and one Caucasian family, respectively, a novel putative pathogenic mutation, p.N1221K, in one Japanese family, and a known nonsynonymous variant, p.G2385R, in two Japanese families. Detailed analysis of the frequency of p.G2385R among 100 Japanese Ad-PD, 73 sporadic PD (sPD) and 238 controls revealed that the frequency of the p.G2385R variant was significantly higher in Ad-PD than in controls (allele frequency, 9.0 vs 2.1%) (χ(2)=16.32, P=5.34 × 10(-5)). The p.G2385R variant, however, did not show complete cosegregation with PD. In addition, the frequency of p.G2385R was also higher in sPD than in controls, although not significant (allele frequency, 3.4 vs 2.1%) (χ(2)=0.76, P=0.38). These observations support the possibility that p.G2385R is associated with an increased risk of PD.