Factors that May Influence SCA8 Disease Penetrance

Possible cis modifiers that could affect penetrance of the SCA8 expansion include d(CTG) repeat length, sequence interruptions within the repeat tract, and the size of the d(CTA) tract preceding the d(CTG) repeat, all of which show remarkable variation independent of haplotype (Ikeda et al. 2000a, b, 2004; Moseley et al. 1998, 2000, 2002).

11.1

The d(CTA) Repeat Tract

A polymorphic but stably transmitted d(CTA) repeat tract containing from one to 21 repeats precedes the d(CTG) expansion, with the overall configuration d(CTA)„d(CTG)exp (Koob et al. 1999; Moseley et al. 2000; Stevanin et al. 2000; Mosemiller et al. 2003). In most studies, a simple PCR assay that detects the overall size of the combined repeats has been used to amplify the SCA8 expansions, with the respective lengths of the d(CTA) and d(CTG) repeat tracts not being determined. Although the SCA8 expansion in the MN-

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Consensus Haplotype A

Caucasian fc 11 I Heroin f Y I Recombinant Haplotype A' — r * * r w/*microsatellite repeat instability

Japanese V V V tCTC)n ' V V "1 Consensus Haplotype B

I Consensus Haplotype C

A and other Caucasian SCA8 expansion families descends from a common founder mutation, a notable molecular difference in the repeat tract of the MN-A family versus that of other families with lower disease penetrance is that the d(CTA) tract is much smaller in the MN-A family (Ikeda et al. 2004), suggesting that the length of the d(CTA) repeat may contribute to differences in disease penetrance. The size variability of both the d(CTA) and d(CTG) repeat tracts makes direct comparisons between repeat length and disease penetrance difficult among families.

11.2

Interruptions Within the d(CTG) Expansion

An unusual feature of the SCA8 expansions is that the expanded alleles often have triplet interruptions within the repeat tract, with one or more d(CCG), d(CTA), d(CTC), d(CCA), or d(CTT) motifs found within the d(CTG) expansion (Moseley et al. 2000; Mosemiller et al. 2003). These interruptions, which are generally clustered at the 5' end of the expansion, often duplicate during transmission—resulting in offspring with alleles that vary from the affected parent both in repeat tract length and sequence configuration. In general, most normal d(CTG) repeat tracts do not have sequence interruptions, although Sobrido et al. (2001) described a normal allele with 23 combined repeats, in which the d(CTG) tract had a d(CAG) interruption. Although both interrupted and pure d(CTG) repeat tracts are found in SCA8 ataxia families, the high frequency of interruptions in the MN-A family suggests that the d(CCG) interruptions in this family may play a role in the relatively high disease penetrance (Moseley et al. 2000).

11.3

Repeat Instability During Transmission

In addition to changes in the sequence of the SCA8 expansion, the SCA8 expansion alleles also show dramatic intergenerational changes in repeat length (Koob et al. 1999; Mosemiller et al. 2003). The changes in SCA8 expansion size are generally larger than in the other dominantly inherited SCAs, but are typically not as large as for DM1 (Tsilfidis et al. 1992; Chung et al. 1993; Maciel et al. 1995; Maruyama et al. 1995; Cancel et al. 1997; David et al. 1997; Jodice et al. 1997; Zhuchenko et al. 1997; Koob et al. 1999). As a general rule, paternal transmissions result in a contraction of the repeat tract (- 86 to + 7), while maternal transmissions result in expansions (- 11 to + 900), with extreme examples of large maternally transmitted increases in repeat length including + 250, + 375, + 600, and + 900 (Koob et al. 1999; Corral et al. 2005). A histogram depicting the intergenerational changes in the repeat length, which distinguishes between maternal and paternal transmission, is shown (Fig. 6). The maternal bias for repeat tract expansion has not been observed for other

SCAs, but is reminiscent of transmission tendencies for two other noncoding expansion disorders—FXS and DM1 (Groenen and Wieringa 1998; Koob et al. 1999; Jin and Warren 2000; Mosemiller et al. 2003).

In the MN-A family the maternal expansion and paternal deletion biases affect disease penetrance, with 90% of the transmissions that resulted in ataxia being maternally transmitted and the remaining 10% involving the transmission of expanded alleles from both parents (Fig. 1) (Koob et al. 1999; Mosemiller et al. 2003). In contrast, 16 of the 19 asymptomatic individuals who carried repeat expansions received the SCA8 expansion from their father. This maternal penetrance bias observed in the MN-A family is consistent with a higher frequency of female transmissions resulting in expansions above the pathogenic threshold of approximately 110 combined repeats, while paternal transmissions tend to result in alleles in which the repeat tract has contracted below the pathogenic threshold (Koob et al. 1999; Day et al. 2000). However, this maternal penetrance bias seen in the MN-A family is not evident in many of the SCA8 families examined (Juvonen et al. 2000).

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□ Maternal Transmissions I Paternal Transmissions

□ Maternal Transmissions I Paternal Transmissions

Fig. 6 Intergenerational variation in repeat number for maternal and paternal transmissions. Repeat variation is shown as a decrease or an increase of CTG repeat units. Maternal and paternal transmissions are represented by gray bars and black bars, respectively. (Reproduced from Koob et al. 1999 with permission from © 1999 Nature Publishing Group (http://www.nature.com/ng/index.html))

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Change in CTG repeat length

Fig. 6 Intergenerational variation in repeat number for maternal and paternal transmissions. Repeat variation is shown as a decrease or an increase of CTG repeat units. Maternal and paternal transmissions are represented by gray bars and black bars, respectively. (Reproduced from Koob et al. 1999 with permission from © 1999 Nature Publishing Group (http://www.nature.com/ng/index.html))

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