Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease

Nichols, William C.; Pankratz, Nathan; Hernandez, Dena G.; Paisán-Ruı́z, Coro; Jain, Sandeep; Halter, Cheryl; Michaels, Veronika E.; Reed, Terry; Rudolph, Alice; Shults, Clifford W.; Singleton, Andrew B.; Foroud, Tatiana

doi:10.1016/s0140-6736(05)17828-3

Cited by 306 publications

(322 citation statements)

References 6 publications

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“…Phenocopies have previously been detected in other families with LRRK2 mutations, including the p.R1441C and the p.G2019S mutation. 9,13,20 The frequent occurrence of phenocopies illustrates the complexity of genetic studies in aetiologically heterogeneous, highly prevalent diseases such as PD.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Human LRRK2 PD-associated mutations are manifest as autosomal dominant [4], and account for a substantial proportion of familial PD and also are implicated in sporadic PD [5][6][7][8][9][10]. Additionally, genome-wide association studies studies have identified a single nucleotide polymorphism closely linked to the LRRK2 locus, suggesting a potential role in sporadic/idiopathic PD [45].…”

Section: Discussionmentioning

confidence: 99%

“…Leucinerich repeat kinase 2 (LRRK2)/Dardarin mutations are linked, as a causative gene, to PD [1][2][3][4]. LRRK2 mutations are estimated to account for 10 % of familial and between 1 % and 3 % of sporadic PD [5][6][7][8][9][10]. LRRK2 proximate single nucleotide polymorphisms have also been significantly associated with idiopathic/sporadic PD by genome-wide association studies [3,4,11].…”

Section: Introductionmentioning

confidence: 99%

“…As the LRRK2 G2019S mutation is causal and contributory to familial and sporadic/idiopathic PD respectively, together accounting for~2 % of all PD in the North American and UK population [7,8] and 20-40 % in certain populations [35][36][37], the development of models that may be predictive in the prosecution of new therapeutics is meritorious. Advancing the development of both small molecules and biologics for PD requires cellular models in which the varying and stable levels of a putative pathogenic gene product can be studied.…”

Section: Introductionmentioning

confidence: 99%

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Development of Inducible Leucine-rich Repeat Kinase 2 (LRRK2) Cell Lines for Therapeutics Development in Parkinson's Disease

et al. 2013

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The pathogenic mechanism(s) contributing to loss of dopamine neurons in Parkinson's disease (PD) remain obscure. Leucine-rich repeat kinase 2 (LRRK2) mutations are linked, as a causative gene, to PD. LRRK2 mutations are estimated to account for 10 % of familial and between 1 % and 3 % of sporadic PD. LRRK2 proximate single nucleotide polymorphisms have also been significantly associated with idiopathic/sporadic PD by genome-wide association studies. LRRK2 is a multidomain-containing protein and belongs to the protein kinase super-family. We constructed two inducible dopaminergic cell lines expressing either human-LRRK2-wild-type or human-LRRK2-mutant (G2019S). Phenotypes of these LRRK2 cell lines were examined with respect to cell viability, morphology, and protein function with or without induction of LRRK2 gene expression. The overexpression of G2019S gene promoted 1) low cellular metabolic activity without affecting cell viability, 2) blunted neurite extension, and 3) increased phosphorylation at S910 and S935. Our observations are consistent with reported general phenotypes in LRRK2 cell lines by other investigators. We used these cell lines to interrogate the biological function of LRRK2, to evaluate their potential as a drug-screening tool, and to investigate screening for small hairpin RNA-mediated LRRK2 G2019S gene knockdown as a potential therapeutic strategy. A proposed LRRK2 kinase inhibitor (i.e., IN-1) decreased LRRK2 S910 and S935 phosphorylation in our MN9DLRRK2 cell lines in a dose-dependent manner. Lentivirus-mediated transfer of LRRK2 G2019S allele-specific small hairpin RNA reversed the blunting of neurite extension caused by LRRK2 G2019S overexpression. Taken together, these inducible LRRK2 cell lines are suitable reagents for LRRK2 functional studies, and the screening of potential LRRK2 therapeutics.

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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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Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease

Cited by 306 publications

References 6 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

Development of Inducible Leucine-rich Repeat Kinase 2 (LRRK2) Cell Lines for Therapeutics Development in Parkinson's Disease

Progress in the pathogenesis and genetics of Parkinson's disease

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