Parkinson Disease: Bras J

Bras J, Singleton A, Cookson MR, Hardy J. · Molecular Genetics Unit, National Institutes on Aging, Bethesda, MD, USA. · FEBS J. · Pubmed #19021754 No free full text.

Abstract: Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis.

Okubadejo N, Britton A, Crews C, Akinyemi R, Hardy J, Singleton A, Bras J. · Neurology Unit, Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria. · PLoS One. · Pubmed #18927607 links to  free full text

Abstract: Several genetic variations have been associated with Parkinson disease in different populations over the past few years. Although a considerable number of worldwide populations have been screened for these variants, results from Sub-Saharan populations are very scarce in the literature. In the present report we have screened a cohort of Parkinson disease patients (n = 57) and healthy controls (n = 51) from Nigeria for mutations in the genes PRKN, LRRK2 and ATXN3. No pathogenic mutations were found in any of the genes. Hence, common pathogenic mutations in these genes, observed in several different populations, are not a frequent cause of Parkinson disease in Nigeria.

Bras J, Simón-Sánchez J, Federoff M, Morgadinho A, Januario C, Ribeiro M, Cunha L, Oliveira C, Singleton AB. · Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD 20892, USA. · Hum Mol Genet. · Pubmed #18923002 No free full text.

Abstract: Mutations in GIGYF2 have recently been described as causative of Parkinson's disease in Europeans. In an attempt to replicate these results in independent populations, we sequenced the entire coding region of GIGYF2 in a large series of Portuguese and North American samples. We report the finding of two of the previously published mutations in neurologically normal Control individuals. This suggests that mutations in GIGYF2 are not strongly related to the development of the disease in either of these populations.

Bras J, Guerreiro R, Ribeiro M, Morgadinho A, Januario C, Dias M, Calado A, Semedo C, Oliveira C, Hardy J, Singleton A. · Center for Neurosciences and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. · BMC Neurol. · Pubmed #18211709 links to  free full text

Abstract: BACKGROUND: Mutations in the genes PRKN and LRRK2 are the most frequent known genetic lesions among Parkinson's disease patients. We have previously reported that in the Portuguese population the LRRK2 c.6055G > A; p.G2019S mutation has one of the highest frequencies in Europe. METHODS: Here, we follow up on those results, screening not only LRRK2, but also PRKN, SNCA and PINK1 in a cohort of early-onset and late-onset familial Portuguese Parkinson disease patients. This series comprises 66 patients selected from a consecutive series of 132 patients. This selection was made in order to include only early onset patients (age at onset below 50 years) or late-onset patients with a positive family history (at least one affected relative). All genes were sequenced bi-directionally, and, additionally, SNCA, PRKN and PINK1 were subjected to gene dosage analysis. RESULTS: We found mutations both in LRRK2 and PRKN, while the remaining genes yielded no mutations. Seven of the studied patients showed pathogenic mutations, in homozygosity or compound heterozygosity for PRKN, and heterozygosity for LRRK2. CONCLUSION: Mutations are common in Portuguese patients with Parkinson's disease, and these results clearly have implications not only for the genetic diagnosis, but also for the genetic counseling of these patients.

Bras J, Paisan-Ruiz C, Guerreiro R, Ribeiro MH, Morgadinho A, Januario C, Sidransky E, Oliveira C, Singleton A. · Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Neurobiol Aging. · Pubmed #18160183 No free full text.

Abstract: Mutations in the gene encoding beta-glucocerebrosidase, a lysosomal degrading enzyme, have recently been associated with the development of Parkinson disease. Here we report the results found in a cohort of Portuguese Parkinson disease patients and healthy age-matched controls for mutations in the aforementioned gene. This screening was accomplished by sequencing the complete open-reading frame, as well as intron/exon boundaries, of the glucocerebrosidase gene, in a total of 230 patients and 430 controls. We have found an increased number of Parkinson disease patients presenting mutations in GBA when compared to controls. These results, together with recent literature, clearly suggest a role of glucocerebrosidase in the development of Parkinson disease.