Scientific publications

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

Oct 28, 2011 | Magazine: Movement Disorders

Lorenzo-Betancor O, Samaranch L, Ezquerra M, Tolosa E, Lorenzo E, Irigoyen J, Gaig C, Pastor MA, Soto-Ortolaza AI, Ross OA, Rodríguez-Oroz MC, Valldeoriola F, Martí MJ, Luquin MR, Perez-Tur J, Burguera JA, Obeso JA, Pastor P.

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.

We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations.

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.

CITATION  Mov Disord. 2011 Oct 28. doi: 10.1002/mds.23968

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