Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

Alessio Di Fonzo, Cristina Tassorelli, Michele De Mari, Hsin F. Chien, Joaquim Ferreira, Christan F. Rohé, Giulio Riboldazzi, Angelo Antonini, Gianni Albani, Alessandro Mauro, Roberto Marconi, Giovanni Abbruzzese, Leonardo Lopiano, Emiliana Fincati, Marco Guidi, Paolo Marini, Fabrizio Stocchi, Marco Onofrj, Vincenzo Toni, Michele TinazziGiovanni Fabbrini, Paolo Lamberti, Nicola Vanacore, Giuseppe Meco, Petra Leitner, Ryan J. Uitti, Zbigniew K Wszolek, Thomas Gasser, Erik J. Simons, Guido J. Breedveld, Stefano Goldwurm, Gianni Pezzoli, Cristina Sampaio, Egberto Barbosa, Emilia Martignoni, Ben A. Oostra, Vincenzo Bonifati, N. Vancore, E. Fabrizio, N. Locuratolo, L. Martini, C. Scoppetta, C. Colosimo, Ma Manfredi, L. Lopiano, A. Tavella, B. Bergamasco, C. Tassorelli, C. Pacchetti, G. Nappi, M. Canesi, D. Calandrella, G. Brono, Mi Manfredi, F. Raudino, E. Corengia, A. Bonizzato, C. Ferracci, A. Dalla Libera, R. Marchese, P. Montagna, S. Ramat, F. Massaro, C. Minardi, F. Rasi, A. Thomas, L. Vacca, F. De Pandis, C. Diroma, G. Iliceto, P. Lamberti, V. Toni, G. Trianni, A. Mauro, A. De Gaetano, M. Rizzo, G. Cossu

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

Original languageEnglish (US)
Pages (from-to)322-331
Number of pages10
JournalEuropean Journal of Human Genetics
Volume14
Issue number3
DOIs
StatePublished - Mar 2006

Fingerprint

Leucine
Parkinson Disease
Phosphotransferases
Mutation
Genes
Phenotype
Genetic Testing
Age of Onset
Open Reading Frames
Disease Progression
Exons
Proteins

Keywords

  • Autosomal dominant
  • Familial
  • LRRK2
  • Mutation
  • PARK8
  • Parkinson

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Di Fonzo, A., Tassorelli, C., De Mari, M., Chien, H. F., Ferreira, J., Rohé, C. F., ... Cossu, G. (2006). Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. European Journal of Human Genetics, 14(3), 322-331. https://doi.org/10.1038/sj.ejhg.5201539

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. / Di Fonzo, Alessio; Tassorelli, Cristina; De Mari, Michele; Chien, Hsin F.; Ferreira, Joaquim; Rohé, Christan F.; Riboldazzi, Giulio; Antonini, Angelo; Albani, Gianni; Mauro, Alessandro; Marconi, Roberto; Abbruzzese, Giovanni; Lopiano, Leonardo; Fincati, Emiliana; Guidi, Marco; Marini, Paolo; Stocchi, Fabrizio; Onofrj, Marco; Toni, Vincenzo; Tinazzi, Michele; Fabbrini, Giovanni; Lamberti, Paolo; Vanacore, Nicola; Meco, Giuseppe; Leitner, Petra; Uitti, Ryan J.; Wszolek, Zbigniew K; Gasser, Thomas; Simons, Erik J.; Breedveld, Guido J.; Goldwurm, Stefano; Pezzoli, Gianni; Sampaio, Cristina; Barbosa, Egberto; Martignoni, Emilia; Oostra, Ben A.; Bonifati, Vincenzo; Vancore, N.; Fabrizio, E.; Locuratolo, N.; Martini, L.; Scoppetta, C.; Colosimo, C.; Manfredi, Ma; Lopiano, L.; Tavella, A.; Bergamasco, B.; Tassorelli, C.; Pacchetti, C.; Nappi, G.; Canesi, M.; Calandrella, D.; Brono, G.; Manfredi, Mi; Raudino, F.; Corengia, E.; Bonizzato, A.; Ferracci, C.; Dalla Libera, A.; Marchese, R.; Montagna, P.; Ramat, S.; Massaro, F.; Minardi, C.; Rasi, F.; Thomas, A.; Vacca, L.; De Pandis, F.; Diroma, C.; Iliceto, G.; Lamberti, P.; Toni, V.; Trianni, G.; Mauro, A.; De Gaetano, A.; Rizzo, M.; Cossu, G.

In: European Journal of Human Genetics, Vol. 14, No. 3, 03.2006, p. 322-331.

Research output: Contribution to journalArticle

Di Fonzo, A, Tassorelli, C, De Mari, M, Chien, HF, Ferreira, J, Rohé, CF, Riboldazzi, G, Antonini, A, Albani, G, Mauro, A, Marconi, R, Abbruzzese, G, Lopiano, L, Fincati, E, Guidi, M, Marini, P, Stocchi, F, Onofrj, M, Toni, V, Tinazzi, M, Fabbrini, G, Lamberti, P, Vanacore, N, Meco, G, Leitner, P, Uitti, RJ, Wszolek, ZK, Gasser, T, Simons, EJ, Breedveld, GJ, Goldwurm, S, Pezzoli, G, Sampaio, C, Barbosa, E, Martignoni, E, Oostra, BA, Bonifati, V, Vancore, N, Fabrizio, E, Locuratolo, N, Martini, L, Scoppetta, C, Colosimo, C, Manfredi, M, Lopiano, L, Tavella, A, Bergamasco, B, Tassorelli, C, Pacchetti, C, Nappi, G, Canesi, M, Calandrella, D, Brono, G, Manfredi, M, Raudino, F, Corengia, E, Bonizzato, A, Ferracci, C, Dalla Libera, A, Marchese, R, Montagna, P, Ramat, S, Massaro, F, Minardi, C, Rasi, F, Thomas, A, Vacca, L, De Pandis, F, Diroma, C, Iliceto, G, Lamberti, P, Toni, V, Trianni, G, Mauro, A, De Gaetano, A, Rizzo, M & Cossu, G 2006, 'Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease', European Journal of Human Genetics, vol. 14, no. 3, pp. 322-331. https://doi.org/10.1038/sj.ejhg.5201539
Di Fonzo, Alessio ; Tassorelli, Cristina ; De Mari, Michele ; Chien, Hsin F. ; Ferreira, Joaquim ; Rohé, Christan F. ; Riboldazzi, Giulio ; Antonini, Angelo ; Albani, Gianni ; Mauro, Alessandro ; Marconi, Roberto ; Abbruzzese, Giovanni ; Lopiano, Leonardo ; Fincati, Emiliana ; Guidi, Marco ; Marini, Paolo ; Stocchi, Fabrizio ; Onofrj, Marco ; Toni, Vincenzo ; Tinazzi, Michele ; Fabbrini, Giovanni ; Lamberti, Paolo ; Vanacore, Nicola ; Meco, Giuseppe ; Leitner, Petra ; Uitti, Ryan J. ; Wszolek, Zbigniew K ; Gasser, Thomas ; Simons, Erik J. ; Breedveld, Guido J. ; Goldwurm, Stefano ; Pezzoli, Gianni ; Sampaio, Cristina ; Barbosa, Egberto ; Martignoni, Emilia ; Oostra, Ben A. ; Bonifati, Vincenzo ; Vancore, N. ; Fabrizio, E. ; Locuratolo, N. ; Martini, L. ; Scoppetta, C. ; Colosimo, C. ; Manfredi, Ma ; Lopiano, L. ; Tavella, A. ; Bergamasco, B. ; Tassorelli, C. ; Pacchetti, C. ; Nappi, G. ; Canesi, M. ; Calandrella, D. ; Brono, G. ; Manfredi, Mi ; Raudino, F. ; Corengia, E. ; Bonizzato, A. ; Ferracci, C. ; Dalla Libera, A. ; Marchese, R. ; Montagna, P. ; Ramat, S. ; Massaro, F. ; Minardi, C. ; Rasi, F. ; Thomas, A. ; Vacca, L. ; De Pandis, F. ; Diroma, C. ; Iliceto, G. ; Lamberti, P. ; Toni, V. ; Trianni, G. ; Mauro, A. ; De Gaetano, A. ; Rizzo, M. ; Cossu, G. / Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. In: European Journal of Human Genetics. 2006 ; Vol. 14, No. 3. pp. 322-331.
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abstract = "Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83{\%} Italian). Pathogenic mutations were identified in six probands (10{\%}): the heterozygous p.G2019S mutation in four (6.6{\%}), and the heterozygous p.R1441C mutation in two (3.4{\%}) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.",
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TY - JOUR

T1 - Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

AU - Di Fonzo, Alessio

AU - Tassorelli, Cristina

AU - De Mari, Michele

AU - Chien, Hsin F.

AU - Ferreira, Joaquim

AU - Rohé, Christan F.

AU - Riboldazzi, Giulio

AU - Antonini, Angelo

AU - Albani, Gianni

AU - Mauro, Alessandro

AU - Marconi, Roberto

AU - Abbruzzese, Giovanni

AU - Lopiano, Leonardo

AU - Fincati, Emiliana

AU - Guidi, Marco

AU - Marini, Paolo

AU - Stocchi, Fabrizio

AU - Onofrj, Marco

AU - Toni, Vincenzo

AU - Tinazzi, Michele

AU - Fabbrini, Giovanni

AU - Lamberti, Paolo

AU - Vanacore, Nicola

AU - Meco, Giuseppe

AU - Leitner, Petra

AU - Uitti, Ryan J.

AU - Wszolek, Zbigniew K

AU - Gasser, Thomas

AU - Simons, Erik J.

AU - Breedveld, Guido J.

AU - Goldwurm, Stefano

AU - Pezzoli, Gianni

AU - Sampaio, Cristina

AU - Barbosa, Egberto

AU - Martignoni, Emilia

AU - Oostra, Ben A.

AU - Bonifati, Vincenzo

AU - Vancore, N.

AU - Fabrizio, E.

AU - Locuratolo, N.

AU - Martini, L.

AU - Scoppetta, C.

AU - Colosimo, C.

AU - Manfredi, Ma

AU - Lopiano, L.

AU - Tavella, A.

AU - Bergamasco, B.

AU - Tassorelli, C.

AU - Pacchetti, C.

AU - Nappi, G.

AU - Canesi, M.

AU - Calandrella, D.

AU - Brono, G.

AU - Manfredi, Mi

AU - Raudino, F.

AU - Corengia, E.

AU - Bonizzato, A.

AU - Ferracci, C.

AU - Dalla Libera, A.

AU - Marchese, R.

AU - Montagna, P.

AU - Ramat, S.

AU - Massaro, F.

AU - Minardi, C.

AU - Rasi, F.

AU - Thomas, A.

AU - Vacca, L.

AU - De Pandis, F.

AU - Diroma, C.

AU - Iliceto, G.

AU - Lamberti, P.

AU - Toni, V.

AU - Trianni, G.

AU - Mauro, A.

AU - De Gaetano, A.

AU - Rizzo, M.

AU - Cossu, G.

PY - 2006/3

Y1 - 2006/3

N2 - Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

AB - Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

KW - Autosomal dominant

KW - Familial

KW - LRRK2

KW - Mutation

KW - PARK8

KW - Parkinson

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