1. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes
- Author
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Tezenas du Montcel, Sophie, Durr, Alexandra, Orsi, Laura, Giunti, Paola, Filla, Alessandro, Szymanski, Sandra, Schöls, Ludger, Klockgether, Thomas, Berciano, José, Pandolfo, Massimo, Boesch, Sylvia, Melegh, Bela, Bauer, Peter, Timmann, Dagmar, Mandich, Paola, Camuzat, Agnès, Ataxia, Clinical Research Consortium for Spinocerebellar, network, EUROSCA, Goto, Jun, Ashizawa, Tetsuo, Cazeneuve, Cécile, Tsuji, Shoji, Pulst, Stefan-M, Figueroa, Karla P, Brusco, Alfredo, Riess, Olaf, Brice, Alexis, Stevanin, Giovanni, Figueroa, Karla, Perlman, Susan, Gomez, Christopher, Wilmot, George, Schmahmann, Jeremy, Ichikawa, Yaeko, Ying, Sarah H, Zesiewicz, Theresa, Paulson, Henry, Shakkottai, Vikram, Bushara, Khalaf, Kuo, Sheng-Han, Geschwind, Michael, Xia, Guangbin, Mazzoni, Pietro, Pulst, Stefan, Brussino, Alessandro, Subramony, S. H., du Montcel, Sophie Tezenas, Forlani, Sylvie, Rakowicz, Maria, Sulek, Anna, Mariotti, Caterina, van de Warrenburg, Bart P C, Bela, Melegh, Baliko, Laszlo, Hadzsiev, Kinga, Tezenas du Montcel, S, Durr, A, Bauer, P, Figueroa, Kp, Ichikawa, Y, Brussino, A, Forlani, S, Rakowicz, M, Sch?ls, L, Mariotti, C, van de Warrenburg, Bp, Orsi, L, Giunti, P, Filla, Alessandro, Szymanski, S, Klockgether, T, Berciano, J, Pandolfo, M, Boesch, S, Melegh, B, Timmann, D, Mandich, P, Camuzat, A, Goto, J, Ashizawa, T, Cazeneuve, C, Tsuji, S, Pulst, Sm, Brusco, A, Riess, O, Brice, A, Stevanin, G, Clinical Research Consortium for Spinocerebellar, Ataxia, and the EUROSCA, Network
- Subjects
Male ,Spinocerebellar Ataxia Type 1 ,Medizin ,ethnology [Asian People] ,Cohort Studies ,Spinocerebellar ataxia type 6 ,diagnosis [Spinocerebellar Ataxias] ,genetics [Spinocerebellar Ataxias] ,Age of Onset ,Child ,Genetics ,ethnology [Spinocerebellar Ataxias] ,Age at onset ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Phenotype ,modifier ,Spinocerebellar ataxia ,trinucleotide repeats ,genetics [European Continental Ancestry Group] ,Female ,Psychology ,Machado–Joseph disease ,genetics [Trinucleotide Repeat Expansion] ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,genetics [White People] ,White People ,Young Adult ,Asian People ,ethnology [European Continental Ancestry Group] ,mental disorders ,medicine ,Humans ,Spinocerebellar Ataxias ,ddc:610 ,Allele ,Aged ,genetics [Asian Continental Ancestry Group] ,ethnology [Asian Continental Ancestry Group] ,genetics [Asian People] ,medicine.disease ,nervous system diseases ,nervous system ,Neurology (clinical) ,ethnology [White People] ,Age of onset ,Trinucleotide repeat expansion ,Trinucleotide Repeat Expansion - Abstract
Item does not contain fulltext Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
- Published
- 2014
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