A new locus for Parkinson's disease (<i>PARK8</i>) maps to chromosome 12p11.2–q13.1

Funayama, Manabu; Hasegawa, Kazuko; Kowa, Hisayuki; Saito, Masaaki; Tsuji, Shoji; Obata, Fumiya

doi:10.1002/ana.10113

Cited by 588 publications

(396 citation statements)

References 23 publications

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“…Previously, linkage to chromosome 12, where LRRK2 is situated, was demonstrated in a Japanese family [208]. In all families, the disease was similar to typical PD with relatively late onset, but there was a wide range of neuropathological findings.…”

Section: Lrrk2 (Park8)mentioning

confidence: 74%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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Section: Lrrk2 (Park8)mentioning

confidence: 74%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…1 A different locus, PARK8 (MIM #607 060), was first mapped to chromosome 12 in a Japanese family with dominantly inherited parkinsonism. 8 Recently, mutations in the gene leucine-rich repeat kinase 2 (LRRK2) (MIM *609 007) have been identified in PARK8-linked families. 9,10 The LRRK2 gene encodes a predicted protein of 2527 amino acids, which has an unknown function.…”

Section: Introductionmentioning

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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“…The vast majority of clinical PD cases are sporadic. Studies of rare familial forms of PD have so far led to the identification of six genes in which mutations can cause PD [4,17,34,36,37,40,54,55,60,65,66,72]. The products of these genes are alpha-synuclein (SNCA), parkin (ubiquitin-conjugating enzyme; UBCH7; PARK2), ubiquitin Cterminal hydrolase L1 (UCHL1), PTEN-induced kinase 1 (PINK), DJ-1 and leucine-rich repeat kinase 2 (LRRK2).…”

Section: Introductionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be upregulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly (ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

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A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1

Cited by 588 publications

References 23 publications

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

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

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

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