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

Partha S. Sarkar, Binoy Appukuttan, Jennifer Han, Yoshihiro Ito, Cuiwei Ai, Wenli Tsai, Yang Chai, J. Timothy Stout, Sita Reddy

Research output: Contribution to journalArticlepeer-review

143 Scopus citations


Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts. The genetic defect in DM is a CTG repeat expansion located in the 3' untranslated region of DMPK and 5' of a home-odomain-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 levels. Second, CTG expansion may establish a region of heterochromatin 3 of the repeat sequence and decrease SIX5 transcription. 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 disorders. 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 α-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.

Original languageEnglish (US)
Pages (from-to)110-114
Number of pages5
JournalNature Genetics
Issue number1
StatePublished - May 2000
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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