LRRK2 R1441G in Spanish patients with Parkinson's disease

Mata, Ignacio; Taylor, Julie P.; Kachergus, Jennifer M.; Hulihan, Mary M.; Huerta, Cecilia; Lahoz, Carlos H.; Blázquez, Marta; Guisasola, Luis M.; Salvador, Carlos; Ribacoba, René; Martı́nez, Carmen; Farrer, Matthew J.; Álvarez, Victoria

doi:10.1016/j.neulet.2005.03.033

Cited by 89 publications

(65 citation statements)

References 10 publications

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“…The occurrence of another two different mutations at the same codon (c.4321C4G, p.R1441G in Basque families, 10,21 , and c.4322G4A, p.R1441H in a sporadic PD case 17 ), is also in keeping with the presence of a mutational hot spot at this position.…”

Section: Discussionmentioning

confidence: 55%

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: 55%

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

et al. 2005

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“…Several studies showed that, although mutations in LRRK2 are most common in all populations, its contribution can vary substantially between different populations [Lesage et al, 2005[Lesage et al, , 2006Mata et al, 2005c;Nuytemans et al, 2008;Ozelius et al, 2006;Zabetian et al, 2005]. The autosomal dominant inheritance of mutations in LRRK2 and the putative gainof-function of these mutations [Gloeckner et al, 2006;Stenmark and Olkkonen, 2001;West et al, 2005], indicates that a CNV for LRRK2 would most likely be a whole-gene multiplication, consistent with a gain-of-function hypothesis.…”

Section: Introductionmentioning

confidence: 82%

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

et al. 2009

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The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.

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“…PD-related LRRK2 gene mutations include R1441C, R1441G, Y1699C, G2019S and I2020T [187][188][189][190][191]. The G2019S and R1141G mutations, which increase kinase activity and decrease GTPase activity, respectively, are the two most common PD-associated mutations in LRRK2 [192][193][194].…”

Section: Lrrk2 (Park8)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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LRRK2 R1441G in Spanish patients with Parkinson's disease

Cited by 89 publications

References 10 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

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

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