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


METHODS
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.
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Oswaldo
O
Lorenzo-Betancor
Lluís
L
Samaranch
Mario
M
Ezquerra
Eduardo
E
Tolosa
Elena
E
Lorenzo
Jaione
J
Irigoyen
Carles
C
Gaig
María A
MA
Pastor
Alexandra I
AI
Soto-Ortolaza
Owen A
OA
Ross
María C
MC
Rodríguez-Oroz
Francesc
F
Valldeoriola
María J
MJ
Martí
María R
MR
Luquin
Jordi
J
Perez-Tur
Juan A
JA
Burguera
José A
JA
Obeso
Pau
P
Pastor
D000328:Adult; D000367:Age Factors; D000368:Aged; D001120:Arginine / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012694:Serine / Q000235:genetics*
D012694:Serine; D001120:Arginine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases