Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease

Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 07/2007; 91(2):195-200. DOI: 10.1016/j.ymgme.2007.03.004
Source: PubMed


An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD).
The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity.
The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R.
These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.

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    • "In immunological analyses of brain tissue from GD patients and GD carriers with parkinsonism, all the samples with GBA mutations showed LB pathology (Shachar et al. 2011). Many other studies in different populations further support the link among GD, PD and LB disorders (Clark et al. 2005; Ziegler et al. 2007; Gan-Or et al. 2008; Mata et al. 2008; Kalinderi et al. 2009; Sidransky et al. 2009; Mitsui et al. 2009; Lesage et al. 2010; Mao et al. 2010). Recently, a strong association between PD and GBA mutations was demonstrated. "
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    ABSTRACT: Gaucher disease is associated with Parkinson's disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases α-synuclein (α-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects α-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between α-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on α-syn and GCase, and it provides some new thoughts that may be helpful for understanding the α-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism.
    Cellular and Molecular Neurobiology 03/2015; 35(6). DOI:10.1007/s10571-015-0176-8 · 2.51 Impact Factor
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    • "This effort to take a comprehensive and even-handed approach to the literatures inclusion may have strengthened the robustness of the findings while it avoided publication bias and minimized heterogeneity. Compared with previous studies [Aharon-Peretz et al., 2004; Lwin et al., 2004; Clark et al., 2005; Sato et al., 2005; Eblan et al., 2006; Toft et al., 2006; Ziegler et al., 2007; Mitsui et al., 2009; Sidransky et al., 2009; Hu et al., 2010; Mao et al., 2010; Nishioka et al., 2010; Lesage et al., 2011; Moraitou et al., 2011; Choi et al., 2012], the current meta-analysis pooled larger sample sizes, analyzed them both combined and separately. The results showed that GBA gene was absolutely significantly associated with PD. "
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    ABSTRACT: This comprehensive meta-analysis was applied to case-control studies of the association between PD and GBA to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. We searched PubMed, Medline, Cochrane Library, reference lists of relevant studies to June 2012, and email contact with authors. For the case-control studies, the authors found 1) support for the association between PD and GBA, both in total group analysis [fixed: OR and 95%CI: 4.825 (3.901-5.968), P < 0.001; random: OR and 95%CI: 4.791 (3.520-6.520), P < 0.001] and in Asia, Europe, Americas, and Israel subgroups analysis [Asia: fixed: OR and 95%CI: 7.495 (4.490-12.511), P < 0.001, random: OR and 95%CI: 7.989 (4.060-15.723), P < 0.001; Americas: fixed: OR and 95%CI: 4.036 (2.460-6.622), P < 0.001, random: OR and 95%CI: 4.065 (2.464-6.707), P < 0.001; Europe: fixed: OR and 95%CI: 3.353 (2.287-4.917), P < 0.001, random: OR and 95%CI: 3.559 (2.148-5.894), P < 0.001; Israel: fixed/random: OR and 95%CI: 6.430 (4.430-9.333), P < 0.001], 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. In conclusion, GBA mutation status may be significantly associated with PD. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2014; 165(1). DOI:10.1002/ajmg.b.32214 · 3.42 Impact Factor
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    • "GBA L444P mutation has reportedly been associated with PD in various ethnic groups [7,9-16,19,20,26]. In a previous study, L444P was identified as the most frequent mutation in non-Ashkenazi Jewish patients [21]. "
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    ABSTRACT: Background Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. Methods In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W). Results Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects. Conclusions Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.
    Behavioral and Brain Functions 12/2012; 8(1):57. DOI:10.1186/1744-9081-8-57 · 1.97 Impact Factor
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