Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease
| Autor: | Ben A. Oostra, Alessandro Mauro, Giuseppe Meco, Joaquim J. Ferreira, Cristina Sampaio, Ryan J. Uitti, Emilia Martignoni, Michele Tinazzi, Marco Guidi, Gianni Pezzoli, Roberto Marconi, Cristina Tassorelli, Giovanni Fabbrini, Stefano Goldwurm, Zbigniew K. Wszolek, Leonardo Lopiano, P. Marini, Christan F. Rohé, Guido J. Breedveld, Vincenzo Bonifati, Marco Onofrj, Thomas Gasser, Giovanni Abbruzzese, Angelo Antonini, Erik J. Simons, Petra Leitner, Giulio Riboldazzi, Vincenzo Toni, G. Albani, Paolo Lamberti, Fabrizio Stocchi, Alessio Di Fonzo, E. Fincati, Nicola Vanacore, Michele De Mari, Hsin F. Chien, Egberto Reis Barbosa |
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| Přispěvatelé: | Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Proband Parkinson PARK8 LRRK2 familial autosomal dominant mutation Heterozygote medicine.medical_specialty Genotype Molecular Sequence Data Protein Serine-Threonine Kinases Biology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 medicine.disease_cause Open Reading Frames Exon Genetic linkage Molecular genetics Genetics medicine Animals Humans Amino Acid Sequence Genetic Testing Gene Genetics (clinical) Aged Genes Dominant lrrk2 park8 parkinson Family Health Mutation Polymorphism Genetic Models Genetic Parkinson Disease Exons Middle Aged Pedigree Protein Structure Tertiary Alternative Splicing Phenotype Disease Progression Medical genetics Female |
| Zdroj: | European Journal of Human Genetics, 14(3), 322-331. Nature Publishing Group |
| ISSN: | 1018-4813 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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