title: Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes.
abstract: 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.
authors.affiliation: Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700064, India.
authors.forename: Biswanath
authors.initials: B
authors.lastname: Chattopadhyay
authors.forename: Kanad
authors.initials: K
authors.lastname: Baksi
authors.forename: Saikat
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Nitai P
authors.initials: NP
authors.lastname: Bhattacharyya
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics; D003851:Deoxyribonucleases / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D043326:Glucan 1,3-beta-Glucosidase; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000235:genetics; D019680:Trinucleotide Repeat Expansion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline; C113696:DFFB protein, human; D003851:Deoxyribonucleases; D043326:Glucan 1,3-beta-Glucosidase; D008239:Lysine