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. 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

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122 Scopus citations


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
Issue number3
StatePublished - Mar 1 2006


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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