Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused 
by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger 
protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, 
ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic 
heterogeneity make molecular diagnosis of DM2 difficult, and yield variable 
clinical phenotypes. To better understand the mutational origin and instability 
of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking 
regions in 26 primate species. The 3'-end of an AluSx element, flanked by target 
site duplications (5'-ACTRCCAR-3'or 5'-ACTRCCARTTA-3'), followed the CCTG 
repeat, suggesting that the repeat was originally derived from the Alu element 
insertion. In addition, our results revealed lineage-specific repetitive motifs: 
pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) 
repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and 
tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. 
Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) 
tail of the AluSx element, and evolved into unstable CCTG repeats during primate 
evolution. Alu elements are known to be the source of microsatellite repeats 
responsible for two other repeat expansion disorders: Friedreich ataxia and 
spinocerebellar ataxia type 10. Taken together, these findings raise questions 
as to the mechanism(s) by which Alu-mediated repeats developed into the large, 
extremely unstable expansions common to these three disorders.