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

Oswaldo Lorenzo-Betancor, Lluís Samaranch, Mario Ezquerra, Eduardo Tolosa, Elena Lorenzo, Jaione Irigoyen, Carles Gaig, María A. Pastor, Alexandra I. Soto-Ortolaza, Owen A. Ross, María C. Rodríguez-Oroz, Francesc Valldeoriola, María J. Martí, María R. Luquin, Jordi Perez-Tur, Juan A. Burguera, José A. Obeso, Pau Pastor

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)146-150
Number of pages5
JournalMovement Disorders
Issue number1
StatePublished - Jan 1 2012


  • Dardarin
  • Genetics
  • Haplotype
  • LRRK2
  • Mutation
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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