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51-59 52-58 51-59

Fig. 4 Meiotic instability of the dodecamer repeat pedigree of the Swiss EPM1 family described by Klein et al. (1968). Carrier and affected status is indicated for the last three generations. All EPM1 alleles share the same haplotype around cystatin B. The number of repeats in the two alleles of tested individuals is shown. Disease alleles are shown in bold. Underlined alleles were subject to meiotic instability. For example, one of the affected children in the far-right branch of the family has two different expanded alleles from both of his siblings unstable during meiosis (Lalioti et al. 1997b). In particular, from the 21 expansions of 12-copy and 13-copy alleles, there are six expansions to alleles with 13, 14, 15, and 17 copies, with the largest expansion being four dode-camers. Although these alleles do not cause EPM1, they can be considered premutation alleles on the basis of their instability. The largest addition observed during transmission of EPM1 alleles is three repeats (Larson et al. 1999). Therefore, large expansions do not seem to be more prone to size increase than premutation alleles.

There is no apparent somatic mosaicism of the repeat in blood DNA from EPM1 patients, excluding extensive mitotic instability. In contrast, three out of six lymphoblastoid cell lines from EPM1 patients showed different alleles from blood of the corresponding patients (Larson et al. 1999).

The dodecamer repeat expansion forms more secondary structures than any of the other triplet repeat expansions, including hairpins, tetraplexes and I-motifs (Jithesh et al. 2001; Pataskar et al. 2001a,b; Saha and Usdin 2001). Tetraplexes, which seem to be the predominant structures of the EPM1 repeat, are stable at physiological temperatures, pH, and ionic strength (Saha and Usdin 2001). These secondary structures formed by intrastrand folding are likely to affect DNA replication and repair and to contribute to the instability of these sequences (Usdin and Grabczyk 2000).

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