Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts

Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, m ental retardation and ocular cataracts(1). The genetic defect in DM is a CT G repeat expansion located in the 3' untranslated region of DMPK and 5' of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5). There are thr ee mechanisms by which CTG expansion can result in DM. First, repeat expans ion may alter the processing or transport of the mutant DMPK mRNA and conse quently reduce DMPK levels(6). Second, CTG expansion may establish a region of heterochromatin 3' of the repeat sequence and decrease SIX5 transcripti on(7-9). Third, toxic effects of the repeat expansion may be intrinsic to t he repeated elements at the level of DNA or RNA (refs 10,11). Previous stud ies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK ho mologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders(12-1 5). To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted. Our results demonstrate that the rate and severi ty of cataract formation is inversely related to Six5 dosage and is tempora lly progressive. Six5(+/-) and Six(5-/-) mice show increased steady-state l evels of the Na+/K+-ATPase alpha-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract fo rmation. As ocular cataracts are a characteristic feature of DM, these resu lts demonstrate that decreased SIX5 transcription is important in the aetio logy of DM. Our data support the hypothesis that DM is a contiguous gene sy ndrome associated with the partial loss of both DMPK and SIX5.