LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation

Background and objective. Mutations in the Leucine‐Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late‐onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late‐onset Parkinson's disease families. Design. We analyzed chromosome 12p11.2‐q13.1 haplotypes in 14 late‐onset Parkinson's disease families without known LRRK2 mutations. Results. Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2‐q13.1 haplotypes. LRRK2 sequencing revealed a novel co‐segregating missense mutation in exon 36 (c.5281A>C; p.S1761R) located within a highly conserved region of the COR [C‐terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC‐COR dimer stability. p.S1761R was present in a late‐onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa‐responsive asymmetrical parkinsonism, with variable age at onset (range: 37–72 years) suggesting age‐dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC‐COR domain dimerization lead to typical Parkinson's disease. © 2011 Movement Disorder Society