Nature Genetics
25, 110 - 114 (2000)
doi:10.1038/75500
Heterozygous loss of Six5 in mice is sufficient to cause ocular cataractsPartha S. Sarkar1, Binoy Appukuttan2, Jennifer Han1, Yoshihiro Ito3, Cuiwei Ai1, Wenli Tsai1, Yang Chai3, J. Timothy Stout2
& Sita Reddy11
Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 2
Division of Ophthalmology, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA. 3
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California, USA.
Correspondence should be addressed to Sita Reddy sitaredd@hsc.usc.eduMyotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts1. The genetic defect in DM is a CTG 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 three mechanisms by which CTG expansion can result in DM. First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels6. Second, CTG expansion may establish a region of heterochromatin 3' of the repeat sequence and decrease SIX5 transcription7,
8,
9. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10,11). Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders12,
13,
14,
15. 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 severity of cataract formation is inversely related to Six5 dosage and is temporally progressive. Six5
+/- and Six5
-/- mice show increased steady-state levels of the Na+/K+-ATPase  -1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM. Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5.
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