RESUMO
Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer's disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Polimorfismo Genético , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , EspanhaRESUMO
Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimer's disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.
