Rastreamento de mutações no gene GBA como fator de risco ao desenvolvimento da doença de Parkinson na população brasileira

• Autor(a) principal: Guimarães, Beatriz de Carvalho
• Data de Publicação: 2012
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/16242
• topic: Parkinson s disease; GBA gene; Risk factor; Glucocerebrosidase; Doença de Parkinson; Gene GBA; Fator de risco; Glicocerebrosidase; CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA

Parkinson s disease is the second most common neurodegenerative disorder, after Alzheimer s disease, with an incidence of 3.3% in Brazilian population over the age of 60 years. It s characterized by the degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of intracellular protein inclusions called Lewy bodies in the surviving neurons. PD has a complex etiology which may involve gene-environment interactions and multiple susceptibility genes. In this context, loss-of-function mutations in the glucocerebrosidase gene (GBA) have been well-validated as important susceptibility factors for PD. This gene is located on 1q21 and comprises 11 exons that encode them lysosomal enzyme glucocerebrosidase. The main objective of our study was to investigate if alterations in the GBA gene constitute a predisposing factor for the development of PD in the Brazilian population. For this, a Brazilian cohort of 126 unrelated PD patients (24 familial and 102 sporadic cases; mean age: 66.4 ± 11.4) were screened for GBA mutations by complete sequencing of the gene s exons and some introns. Seven alterations and one recombinant allele, previously found in PD patients performed in other studies, were detected (K(-)27R, IVS2+1G>A, N370S, L444P, T369M, A456P, E326K e RecNciI), as well as, a variant never identified in PD patients (G325G) and one newly identified variant (W378C), in a total of 18 patients (14.3%). In addition, were found three intronic changes (c.454 +47 G>A, c.589- 86A>G and c.1225-34C>A), which are present in the database of SNPs, however, were not associated with any disease. Among all the variants identified, three are proven pathogenic (IVS2 +1 G>A, N370S and L444P) and were found in 5.5% of the sample and not detected in the control sample, indicating a significantly higher frequency of these mutations in patients with PD compared to controls (P = 0.0033). Our results, have strengthened the association between the GBA gene and PD in the Brazilian population, in addition to support the hypothesis that alterations in this gene represent a significant genetic susceptibility factor for the development of PD