Relevant conflicts of interest/financial disclosures: The authors declare no conflicts of interest to report. L.S. held a “Torres Quevedo” fellowship from the Spanish Ministry of Science and Technology, co-financed by the European Social Fund. This study was supported by grants from the Spanish Ministry of Science and Innovation SAF2006-10126 (2006-2009) and SAF2010-22329-C02-01 (2011-2013) to P.P. and SAF2010-10434 (2010-2012) to J.P.T., by the project 061131 from the “Fundació La Marató de TV3” and by the UTE project FIMA, Spain to P.P. Sample collection at Nodo ENAE was partially funded by a grant from the Generalitat Valenciana (07/2008) to J.A.B.
LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation†
Article first published online: 28 OCT 2011
Copyright © 2011 Movement Disorder Society
Volume 27, Issue 1, pages 146–150, January 2012
How to Cite
Lorenzo-Betancor, O., Samaranch, L., Ezquerra, M., Tolosa, E., Lorenzo, E., Irigoyen, J., Gaig, C., Pastor, M. A., Soto-Ortolaza, A. I., Ross, O. A., Rodríguez-Oroz, M. C., Valldeoriola, F., Martí, M. J., Luquin, M. R., Perez-Tur, J., Burguera, J. A., Obeso, J. A. and Pastor, P. (2012), LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation. Mov. Disord., 27: 146–150. doi: 10.1002/mds.23968
- Issue published online: 13 JAN 2012
- Article first published online: 28 OCT 2011
- Parkinson's disease;
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.
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. © 2011 Movement Disorder Society