Genetic Characteristics

Repeat Instability

Normal alleles are usually transmitted to progeny without modification and are similar in size in all tissues. There is, however, a mosaicism of the size of most expansions (except for SCA6) that can be visualized in somatic, including the central nervous system, and gonadic tissues.

When visualized in leukocytes, expansions have a tendency to increase in successive generations, the mean ranging from approximately +1 for SCA3/MJD to +12 repeats for SCA7 (Fig. 1 and Table 2). At the SCA1, SCA2 and SCA7 loci, there is a tendency for greater instability during paternal than during maternal transmissions (Table 2), particularly for the largest expansions (> 20 CAG units).

CAG repeat instability is thought to result from slippage during DNA replication or from the formation of stable hairpin structures.49,50 However, a recent study in an animal model of HD revealed that the mosaicism in post-mitotic neurons increases with age, suggesting that instability does not solely occur during replication.51 The differences in instability among polyQ diseases and the increased instability in paternal transmissions indicates that other factors play a role. Instability is influenced by the size of the repeat required to form stable structures, as demonstrated in HD and SCA7.52,53 In SCA3/MJD, the analysis of polymorphisms located close to the CAG repeat showed that they act both in trans and in cis.54,55

Figure 3. Age at onset/CAG repeat number correlation curves in spinocerebellar ataxias. From reference 3 by courtesy of the Nature Publishing Group.

The greater number of cell divisions in spermatogenesis than in oogenesis is probably another factor. Indeed, mosaicism in gonads56 is much more pronounced than that observed following an analysis of parent-child transmissions. Whole or single sperm studies revealed much greater mosaicism of the expansion at the SCA7 locus than at the SCA3/MJD locus (Fig. 2), which is in accordance with the differences observed in leukocytes during transmissions.53,55,57 The massive CAG expansions in SCA7 may lead to embryonic lethality or dysfunctional sperm,58 as suggested

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