TY - JOUR
T1 - Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes
AU - Du Montcel, Sophie Tezenas
AU - Durr, Alexandra
AU - Bauer, Peter
AU - Figueroa, Karla P.
AU - Ichikawa, Yaeko
AU - Brussino, Alessandro
AU - Forlani, Sylvie
AU - Rakowicz, Maria
AU - Schöls, Ludger
AU - Mariotti, Caterina
AU - Van De Warrenburg, Bart P C
AU - Orsi, Laura
AU - Giunti, Paola
AU - Filla, Alessandro
AU - Szymanski, Sandra
AU - Klockgether, Thomas
AU - Berciano, José
AU - Pandolfo, Massimo
AU - Boesch, Sylvia
AU - Melegh, Bela
AU - Timmann, Dagmar
AU - Mandich, Paola
AU - Camuzat, Agnès
AU - Goto, Jun
AU - Ashizawa, Tetsuo
AU - Cazeneuve, Cécile
AU - Tsuji, Shoji
AU - Pulst, Stefan M.
AU - Brusco, Alfredo
AU - Riess, Olaf
AU - Brice, Alexis
AU - Stevanin, Giovanni
PY - 2014/9
Y1 - 2014/9
N2 - 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.
AB - 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.
KW - Age at onset
KW - Modifier
KW - Spinocerebellar ataxia
KW - Trinucleotide repeat
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U2 - 10.1093/brain/awu174
DO - 10.1093/brain/awu174
M3 - Article
C2 - 24972706
AN - SCOPUS:84906706640
SN - 0006-8950
VL - 137
SP - 2444
EP - 2455
JO - Brain
JF - Brain
IS - 9
ER -