Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease

Department of Neuropsychiatry, Okayama University, Okayama, Okayama, Japan
Neurology (Impact Factor: 8.29). 09/2006; 67(4):697-9. DOI: 10.1212/01.wnl.0000227732.37801.d4
Source: PubMed


LRRK2 G2019S is the most common known cause of Parkinson disease (PD) in patients of European origin, but little is known about its distribution in other populations. The authors identified two of 586 Japanese patients with PD heterozygous for the mutation who shared a haplotype distinct from that observed in Europeans. This suggests that G2019S originated from separate founders in Europe and Japan and is more widely dispersed than previously recognized.

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Available from: Yuishin Izumi, Sep 07, 2015
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    • "Haplotype 1 is the most frequent, predominant in European Americans, North African Arabs, and Ashkenazi Jews, resulting from a common founder (Kachergus et al., 2005), initially dated to 725 years by Lesage et al. (2005) and reevaluated to 2,250 years by Zabetian et al. (2006a). Haplotype 2, being rarer, is shared by few cases among Western Europeans, and haplotype 3 found in the Japanese population (Zabetian et al., 2006b) and recently also in a Turkish family (Pirkevi et al., 2009). Another LRRK2 mutation, shown to be arisen from a common descent, is the R1441C, which lies in the ROC domain. "
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A progressive movement disorder typified by the production of bradykinesia, tremor, rigidity, and impairment of postural reflexes, PD is characterized by a depletion of dopamine in the striatum. For the last decade, several Mendelian forms of PD have been identified. Mutations in these genes potentially lead to autosomal dominant (alpha-synuclein and LRRK2), or autosomal recessive PD (Parkin, PINK1, DJ1, and ATP13A2). This article will spotlight these six distinct genes unambiguously associated with Mendelian PD and the function of their encoded proteins.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2009; 292(12):1893-901. DOI:10.1002/ar.20968 · 1.54 Impact Factor
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    • " from at least three haplotypes . Most patients carrying this mutation and living in disparate countries in Europe and in North America share a common , ancient founder haplotype , which likely originated from North Africa or the Middle East 2 , 000 years ago or earlier ( Goldwurm et al . , 2005 ; Kachergus et al . , 2005 ; Lesage et al . , 2005 ; Zabetian et al . , 2006b ) . A second haplotype has been detected in a few patients of European ancestry , and a third haplotype was found in Japanese patients ( Zabetian et al . , 2006a , b ) . The occurrence of the G2019S mutation in at least three haplotypes suggests either an extremely old founder or a mutational hot spot . The penetrance of the LRRK2 G2019"
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    ABSTRACT: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, with a prevalence of more than 1% after the age of 65 years. Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have recently been linked to autosomal dominant, late-onset PD that is clinically indistinguishable from typical, idiopathic disease. LRRK2 is a multidomain protein containing several protein interaction motifs as well as dual enzymatic domains of GTPase and protein kinase activities. Disease-associated mutations are found throughout the multidomain structure of the protein. LRRK2, however, is unique among the PD-causing genes, because a missense mutation, G2019S, is a frequent determinant of not only familial but also sporadic PD. Thus, LRRK2 has emerged as a promising therapeutic target for combating PD. In this Mini-Review, we look at the current state of knowledge regarding the domain structure, amino acid substitutions, and potential functional roles of LRRK2.
    Journal of Neuroscience Research 05/2009; 87(6):1283-95. DOI:10.1002/jnr.21949 · 2.59 Impact Factor
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    • "In addition, a common haplotype surrounding the p.Gly2019Ser mutation has been reported, suggesting that it may have an ancestral founder [Goldwurm et al., 2005; Hernandez et al., 2005; Kachergus et al., 2005; Lesage et al., 2005]. Nevertheless, two additional, rare p.Gly2019Ser-associated haplotypes have also been described: a haplotype shared by five European PD families [Zabetian et al., 2006a] and a Japanese-specific haplotype [Tomiyama et al., 2006; Zabetian et al., 2006b] recently found to be shared by a Turkish family [Pirkevi et al., in press]. The p.Gly2019Ser-associated haplotype has been estimated to have lived 2,250 and 3,120 years ago by two independent groups using a maximum-likelihood method and the 30-year intergeneration interval [Warren et al., 2008; Zabetian et al., 2006a]. "
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    ABSTRACT: Mutation in the LRRK2 gene is a known genetic cause of Parkinson disease (PD). However, due to the high frequency in which the most frequent LRRK2 mutation is present and the large size of LRRK2 gene, a complete sequence-based screening of the entire coding region has only been performed by a few researchers. In addition, normal variability in the LRRK2 gene has only been fully assessed in the North American population. Although a complete examination of the entire gene is required to assess the exact contribution of LRRK2 to the etiology of PD, more than 50 variants have been reported to date within the LRRK2 locus. Gene multiplications or deletions have not been reported so far. Here, all LRRK2 variants reported are interpreted and their contribution to the disease is examined.
    Human Mutation 05/2009; 30(8):1153-60. DOI:10.1002/humu.21038 · 5.14 Impact Factor
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