Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease
Department of Neuropsychiatry, Okayama University, Okayama, Okayama, JapanNeurology (Impact Factor: 8.29). 09/2006; 67(4):697-9. DOI: 10.1212/01.wnl.0000227732.37801.d4
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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- "This mutation is present on only a limited number of haplotypes (Lesage and Brice 2009), of which the commonest , referred to as haplotype 1, is thought to have originated in the Ashkenazi Jewish population (Lesage et al. 2010). Two other G2019S-carrying haplotypes have been found in three families of European descent (haplotype 2, Zabetian et al. 2006a) and in one Turkish and two Japanese patients (haplotype 3, Zabetian et al. 2006b; Pirkevi et al. 2009). Mainly due to founder effects, the prevalence of G2019S is 37–41% in North African Arab PD patients (Lesage et al. 2006, 2008) and 10–27% in Ashkenazi Jewish PD patients (Orr-Urtreger et al. 2007; Ozelius et al. 2006). "
ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most significant genetic cause of Parkinson's disease (PD). The exact function of LRRK2 is currently unknown but the presence of multiple protein interaction domains including WD40 and ankyrin indicates that it may act a scaffold for assembly of a multi-protein signaling complex. The G2019S mutation in LRRK2 represents the most clinically relevant PD-causing mutation and has been found in both familial and sporadic forms of the disorder. This mutation is situated in the highly conserved kinase MAPKKK domain, and has been found in up to 40% of PD patients from North African Arabic, 30% of Ashkenazi Jewish and approximately 10% of Portuguese and Spanish populations. Although extensively investigated in numerous European and North American populations, studies on the frequency of G2019S in African countries have been rare. The present study is the first on the South African population. High-resolution melt analysis was used to identify the G2019S mutation and it was found in 2% (4/205) of the patients studied. G2019S was not found in any of the Black PD patients screened. In all four G2019S-positive probands the mutation was shown to be present on the common haplotype referred to as haplotype 1. This reveals that the four South African G2019S-positive probands (three Caucasian and one of mixed ancestry) share a common ancestor with the other haplotype 1-associated families reported worldwide.
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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. "
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.
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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"
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.