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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume27
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Leucine
Haplotypes
Parkinson Disease
Phosphotransferases
Mutation
Chromosomes
ras Proteins
Penetrance
Parkinsonian Disorders
Dimerization
Levodopa
Missense Mutation
Age of Onset
Exons
Late Onset Disorders
Genes

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Lorenzo-Betancor, O., Samaranch, L., Ezquerra, M., Tolosa, E., Lorenzo, E., Irigoyen, J., ... Pastor, P. (2012). LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation. Movement Disorders, 27(1), 146-150. https://doi.org/10.1002/mds.23968

LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation. / Lorenzo-Betancor, Oswaldo; Samaranch, Lluís; Ezquerra, Mario; Tolosa, Eduardo; Lorenzo, Elena; Irigoyen, Jaione; Gaig, Carles; Pastor, María A.; Soto-Ortolaza, Alexandra I.; Ross, Owen A; Rodríguez-Oroz, María C.; Valldeoriola, Francesc; Martí, María J.; Luquin, María R.; Perez-Tur, Jordi; Burguera, Juan A.; Obeso, José A.; Pastor, Pau.

In: Movement Disorders, Vol. 27, No. 1, 01.2012, p. 146-150.

Research output: Contribution to journalArticle

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 2012, 'LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation', Movement Disorders, vol. 27, no. 1, pp. 146-150. https://doi.org/10.1002/mds.23968
Lorenzo-Betancor O, Samaranch L, Ezquerra M, Tolosa E, Lorenzo E, Irigoyen J et al. LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation. Movement Disorders. 2012 Jan;27(1):146-150. https://doi.org/10.1002/mds.23968
Lorenzo-Betancor, Oswaldo ; Samaranch, Lluís ; Ezquerra, Mario ; Tolosa, Eduardo ; Lorenzo, Elena ; Irigoyen, Jaione ; Gaig, Carles ; Pastor, María A. ; Soto-Ortolaza, Alexandra I. ; Ross, Owen A ; Rodríguez-Oroz, María C. ; Valldeoriola, Francesc ; Martí, María J. ; Luquin, María R. ; Perez-Tur, Jordi ; Burguera, Juan A. ; Obeso, José A. ; Pastor, Pau. / LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation. In: Movement Disorders. 2012 ; Vol. 27, No. 1. pp. 146-150.
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AU - Tolosa, Eduardo

AU - Lorenzo, Elena

AU - Irigoyen, Jaione

AU - Gaig, Carles

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AU - Soto-Ortolaza, Alexandra I.

AU - Ross, Owen A

AU - Rodríguez-Oroz, María C.

AU - Valldeoriola, Francesc

AU - Martí, María J.

AU - Luquin, María R.

AU - Perez-Tur, Jordi

AU - Burguera, Juan A.

AU - Obeso, José A.

AU - Pastor, Pau

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N2 - 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.

AB - 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.

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