A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease

Fonzo, Alessio Di; Rohé, Christan F.; Ferreira, Joaquim J.; Chien, Hsin Fen; Vacca, Laura; Stocchi, Fabrizio; Guedes, Leonor Correia; Fabrizio, Edito; Manfredi, M.; Vanacore, Nicola; Goldwurm, Stefano; Breedveld, Guido J.; Sampaio, Cristina; Meco, Giuseppe; Barbosa, Egberto Reis; Oostra, Ben A.; Bonifati, Vincenzo

doi:10.1016/s0140-6736(05)17829-5

Cited by 482 publications

(322 citation statements)

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“…Initial results concerning the four families with the p.G2019S mutation have been previously published by us, 12 whereas the other three families with LRRK2 mutations as well as the results of the comprehensive analysis of the LRRK2 gene in the entire sample of 60 ADPD probands are reported here for the first time.…”

Section: Genetic Studiesmentioning

confidence: 84%

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

et al. 2005

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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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Section: Genetic Studiesmentioning

confidence: 84%

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

et al. 2005

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“…In Caucasians, p.G2019S is the most frequent in both Ad-PD and sPD, accounting for B5% of Ad-PD patients and 1.6% of sPD patients. 8,9,18 Many of the patients from European populations share a common haplotype, suggesting that they have a common founder originating in the Near East at least 4000 years ago. 19,20 In contrast, no single mutation has been reported as being predominant in Asian populations.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of the entire 51 exons of LRRK2 by the conventional direct nucleotide sequencing method, however, is very laborious. Therefore, the majority of previous studies have focused on particular exons for mutational analysis, [8][9][10][11][12] making it difficult to obtain accurate data on the molecular epidemiology of Ad-PD caused by LRRK2.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

et al. 2011

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“…PARK8-linked PD is now believed to be the most common form of autosomal dominant familial PD and 20 missense or nonsense mutations have been reported (Paisan-Ruiz et al 2004;Zimprich et al 2004;Aasly et al 2005;Di Fonzo et al 2005;Funayama et al 2005;Hernandez et al 2005;Kachergus et al 2005;Nichols et al 2005;Paisan-Ruiz et al 2005;Mata et al 2006). lrrk2 Mutations were also found in some of the apparently sporadic PD patients (Gilks et al 2005).…”

Section: ; Canet-avilesmentioning

confidence: 99%

Progress in the pathogenesis and genetics of Parkinson's disease

Mizuno

Hattori

Kubo

et al. 2008

Phil. Trans. R. Soc. B

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Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1-linked PD due to a-synuclein (SNCA) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of a-synuclein. In PARK1-linked PD, mutant a-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

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A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease

Cited by 482 publications

References 5 publications

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

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

Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

Progress in the pathogenesis and genetics of Parkinson's disease

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