RESUMO
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1 This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.
Assuntos
Expansão das Repetições de DNA , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Histona Acetiltransferases/genética , Retroelementos , Elementos Nucleotídeos Curtos e Dispersos , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Ordem dos Genes , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Modelos Biológicos , Linhagem , Fenótipo , Regiões Promotoras Genéticas , Ativação TranscricionalRESUMO
The goal of the present study was to examine the utility of a behavioral economic analysis to investigate the role of delay discounting in texting while driving. A sample of 147 college students completed a survey to assess how frequently they send and read text messages while driving. Based on this information, students were assigned to one of two groups: 19 students who frequently text while driving and 19 matched-control students who infrequently text while driving but were similar in gender, age, years of education, and years driving. The groups were compared on the extent to which they discounted, or devalued, delayed hypothetical monetary rewards using a delay-discounting task. In this task, students made repeated choices between $1000 available after a delay (ranging from 1 week to 10 years) and an equal or lesser amount of money available immediately. The results show that the students who frequently text while driving discounted delayed rewards at a greater rate than the matched control students. The study supports the conclusions that texting while driving is fundamentally an impulsive choice made by drivers, and that a behavioral economic approach may be a useful research tool for investigating the decision-making processes underlying risky behaviors.
