Variation of age at onset (AO) in Huntington's disease (HD) cannot be explained by the number of CAG repeats alone in the mutant alleles of the gene huntingtin (Htt). Given the ability of expanded polyglutamine (poly-Q) tract present in Htt protein to interact with other proteins and increased neuronal cell death by apoptosis, variations in the genes coding for htt-interacting proteins and those involved in apoptosis are likely to alter the AO in HD. In the present investigation, we studied two single nucleotide polymorphisms (SNPs), namely, R72P in TP53 gene coding for transcription factor p53, which interacts with Htt protein and R196K in human caspase activated DNase (hCAD) gene involved in apoptosis to investigate their role as genetic modifiers of the AO of HD. Multiple linear regression analysis revealed that variations in TP53 and hCAD genes explained 12.6% and 6%, respectively, of the variance in the AO of HD after accounting for the effect of expanded CAG repeats. Statistical analysis further showed a significant effect of the interaction term between expanded CAG repeats and variations at each of TP53 and hCAD genes upon the AO. This data demonstrated that variations in TP53 and hCAD genes modulate the AO of HD.
"In contrast, SNP's in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have been associated with late onset of the disease (Naze et al., 2002). Age-ofonset has also been associated with SNP's in p53 (Chattopadhyay et al., 2005), hCAD (Chattopadhyay et al., 2005), ASK1 (Arning et al., 2008), MAP2K6 (Arning et al., 2008), APOE (Kehoe et al., 1999), HAP1 (Metzger et al., 2008) and PGC1␣ (Taherzadeh-Fard et al., 2009). Drosophila models of HD may also be a robust model in which to examine exactly how these genes affect mutant Htt-mediated aggregation and neurodegeneration. "
"Less clear in their implications for defining early steps in pathogenesis are a number of reported positive results that appear to implicate such processes as glutamatergic transmission (GRIK2, GRIN2A, GRIN2B) [25-31], protein degradation (UCHL1) [31,32], gene transcription (TCERG1, TP53) [33,34], stress response/apoptosis (DFFB, MAP3K5, MAP2K6) [34,35], lipoprotein metabolism (APOE) , axonal trafficking (HAP1) , folate metabolism (MTHFR) , and energy metabolism (PPARGC1A) [39,40] as having small effects on age at motor onset. In some cases, gender stratification implied a sex-specific effect (APOE, GRIN2A, GRIN2B, MAP2K6) [30,35,36]. "
[Show abstract][Hide abstract] ABSTRACT: For almost three decades, Huntington's disease has been a prototype for the application of genetic strategies to human disease. HD, the Huntington's disease gene, was the first autosomal defect mapped using only DNA markers, a finding in 1983 that helped to spur similar studies in many other disorders and contributed to the concept of the human genome project. The search for the genetic defect itself pioneered many mapping and gene-finding technologies, and culminated in the identification of the HD gene, its mutation and its novel protein product in 1993. Since that time, extensive investigations into the pathogenic mechanism have utilized the knowledge of the disease gene and its defect but, with notable exceptions, have rarely relied for guidance on the genetic findings in human patients to interpret the relevance of findings in non-human model systems. However, the human patient still has much to teach us through a detailed analysis of genotype and phenotype. Such studies have implicated the existence of genetic modifiers - genes whose natural polymorphic variation contributes to altering the development of Huntington's disease symptoms. The search for these modifiers, much as the search for the HD gene did in the past, offers to open new entrées into the process of Huntington's disease pathogenesis by unlocking the biochemical changes that occur many years before diagnosis, and thereby providing validated target proteins and pathways for development of rational therapeutic interventions.
Genome Medicine 09/2009; 1(8):80. DOI:10.1186/gm80 · 5.34 Impact Factor
"Some localized clusters are of interest. One that is considerably down-regulated is on Chr1.p36-p35 and contains MTHFR, CASP9, DFFB, FRAP1 and SHDB genes that have been linked to HD (Kiechle et al., 2002; Brune et al., 2004; Ravikumar et al., 2004; Chattopadhyay et al., 2005; Majumder et al., 2006). Among these genes, only MTHFR individual expression was significantly down-regulated and passed false discovery rate multiple correction (mean expression ratio HD versus controls = 0.55, P = 0.0037). "
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread transcriptional dysregulation. Mutant huntingtin also interacts with histone acetyltransferases, consequently interfering with the acetylation and deacetylation states of histones. Because histone modifications and chromatin structure coordinate the expression of gene clusters, we have applied a novel mathematical approach, Chromowave, to analyse microarray datasets of brain tissue and whole blood to understand how genomic regions are altered by the effects of mutated huntingtin on chromatin structure. Results show that, in samples of caudate and whole blood from Huntington's disease patients, transcription is indeed deregulated in large genomic regions in coordinated fashion, that transcription in these regions is associated with disease progression and that altered chromosomal clusters in the two tissues are remarkably similar. These findings support the notion of a common genome-wide mechanism of disruption of RNA transcription in the brain and periphery of Huntington's disease patients.
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