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. 2014 Sep;137(Pt 9):2444-55.
doi: 10.1093/brain/awu174. Epub 2014 Jun 26.

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Sophie Tezenas du Montcel  1 , Alexandra Durr  2 , Peter Bauer  3 , Karla P Figueroa  4 , Yaeko Ichikawa  5 , Alessandro Brussino  6 , Sylvie Forlani  7 , Maria Rakowicz  8 , Ludger Schöls  9 , Caterina Mariotti  10 , Bart P C van de Warrenburg  11 , Laura Orsi  12 , Paola Giunti  13 , Alessandro Filla  14 , Sandra Szymanski  15 , Thomas Klockgether  16 , José Berciano  17 , Massimo Pandolfo  18 , Sylvia Boesch  19 , Bela Melegh  20 , Dagmar Timmann  21 , Paola Mandich  22 , Agnès Camuzat  7 ; Clinical Research Consortium for Spinocerebellar Ataxia (CRC-SCA); EUROSCA network; Jun Goto  5 , Tetsuo Ashizawa  23 , Cécile Cazeneuve  24 , Shoji Tsuji  5 , Stefan-M Pulst  4 , Alfredo Brusco  6 , Olaf Riess  3 , Alexis Brice  25 , Giovanni Stevanin  26
Collaborators, Affiliations

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Sophie Tezenas du Montcel et al. Brain. 2014 Sep.

Abstract

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.

Keywords: age at onset; modifier; spinocerebellar ataxia; trinucleotide repeat.

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Figures

Figure 1
Figure 1
Histograms of the normal and expanded allele repeat lengths for ATXN1, ATXN2, ATXN3, CACNA1A and ATXN7 in affected individuals of the EUROSCA kindreds.
Figure 2
Figure 2
Histograms of the normal and expanded allele repeat lengths for TBP, ATN1 and HTT in affected individuals of the EUROSCA kindreds.
Figure 3
Figure 3
Modification of the age at onset due to ATXN3 genotypes (expanded allele) in SCA3 cases from the EUROSCA population and the three replication populations. (Top left) EUR: Model parameters: Log(age at onset) (LOA) = −3.8098 + 0.1880 Exp−0.00159 Exp2. (Top right) USA: Model parameters: Log(age at onset) = −5.9960 + 0.2423 Exp–0.00191 Exp2. (Bottom left) Japan: Model parameters: Log(age at onset) = −3.3923 + 0.1684 Exp–0.00137 Exp2. (Bottom right) France: Model parameters: Log(age at onset) = −4.1042 + 0.1951 Exp–0.00162 Exp2. With Exp = Expanded ATXN3 allele.
Figure 4
Figure 4
The presence of at least one ATXN7 allele ≥12 CAG results in an earlier age at onset in SCA2 cases. Open circles and solid lines: no ATXN7 alleles with 12 CAG repeats or more; Crosses and dotted lines: at least one ATXN7 alleles with 12 CAG repeats or more. Model parameters: (A) EUROSCA: Cases with no alleles with both ATXN7 alleles over 12: LOA = 3.318 −0.046 Exp; Cases with at least one allele ≥ 12 repeats: LOA = 3.275 −0.046 Exp. (B) USA: Cases with no alleles with both ATXN7 alleles over 12: LOA = 3.361 −0.045 Exp; Cases with at least one allele ≥ 12 repeats: LOA = 3.331 −0.045 Exp. (C) Italy: Cases with no alleles with both ATXN7 alleles over 12: LOA = 3.120 −0.040 Exp; Cases with at least one allele ≥ 12 repeats: LOA = 3.166 −0.040 Exp. (D) France: Cases with no alleles with both ATXN7 alleles over 12: LOA = 2.949 −0.035 Exp; Cases with at least one allele ≥ 12 repeats: LOA = 2.914 −0.035 Exp. With LOA = Log(Age at onset), Exp = ATXN2 expanded allele.
Figure 5
Figure 5
Summary of interactions among (CAG)n-containing genes in the EUROSCA cohort. For the SCA type, the black labels indicate the gene, the blue label, the age at onset of individuals with an expansion of the gene. Black arrows are for marginal effect whether green arrows are for effect in interaction with the major gene. Nb > 12: = alleles with more than 12 repeats; Interm = intermediate allele; + = positive effect; – = negative effect; Shorter = shorter allele; Longer = longer allele; Longer > 25 = longer allele with >25 repeats; Difference = difference between the longer and the shorter allele.
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References

    1. Aziz NA, Jurgens CK, Landwehrmeyer GB, EHDN Registry Study Group. van Roon-Mom WM, van Ommen GJ, et al. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology. 2009;73:1280–5. - PubMed
    1. Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, et al. Modulation of age at onset in Huntington’s disease and spinocerebellar ataxia type 2 patients originated from eastern India. Neurosci Lett. 2003;345:93–6. - PubMed
    1. de Castilhos RM, Furtado GV, Gheno TC, Schaeffer P, Russo A, Barsottini O, et al. Spinocerebellar ataxias in Brazil–frequencies and modulating effects of related genes. Cerebellum. 2014;13:17–28. - PubMed
    1. de Chiara C, Rees M, Menon RP, Pauwels K, Lawrence C, Konarev PV, et al. Self-assembly and conformational heterogeneity of the AXH domain of ataxin-1: an unusual example of a chameleon fold. Biophys J. 2013;104:1304–13. - PMC - PubMed
    1. Deka R, Miki T, Yin SJ, McGarvey ST, Shriver MD, Bunker CH, et al. Normal CAG repeat variation at the DRPLA locus in world populations. Am J Hum Genet. 1995;57:508–11. - PMC - PubMed

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