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Age at onset of Huntington disease is not modulated by the R72P variation in TP53 and the R196K variation in the gene coding for the human caspase activated DNase (hCAD)

DOI: 10.1186/1471-2350-6-35

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Abstract:

We have genotyped the polymorphisms R72P and R196K in a well established cohort of 167 unrelated HD patients.The expanded CAG repeat explained 30.8% of the variance in AO. Adding the genotypes of the SNPs investigated did not affect the variance of the AO variance explained.In this replication study, no association was found explaining a significant amount of the variability in AO of HD thus contradicting a recent report.Huntington disease (HD) is an autosomal dominantly transmitted, neurodegenerative disorder characterized by motor abnormalities, cognitive dysfunction and psychiatric symptoms [1]. HD is caused by an expansion of a polyglutamine tract in the amino-terminal portion of the protein huntingtin (htt), which apparently acquires a deleterious gain of function [2]. The length of the polyglutamine tract is the most important factor in determining AO of HD, although substantial variability remains after controlling for repeat length, particularly in cases where CAG repeat numbers range in the high 30 s or low 40 s [3]. Therefore, defining independent AO modifying factors is of great importance, since they may provide further clues pertaining to the pathology arising from the expanded repeats. In mammals, TP53 is the most important tumor suppressor gene. A variety of intracellular stress signals activate TP53 to induce either transient cell cycle arrest with stimulation of repair activities, senescence or apoptosis [4]. It has been proposed that the amino-terminal portion of mutant htt encoded by exon 1 exertsfunctional properties with significant consequences for the TP53 pathway in HD neurons. The pathogenic domain of mutant htt interacts with critical transcription factors and potentially modulates TP53-induced transcriptional events [5]. It has been shown that the two variations of the common codon 72 polymorphism (Arg /Pro) in the TP53 gene differ with respect to the ability to suppress cellular transformation [6] and induce apoptosis [7]. Therefore, the

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