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Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy

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Abstract

Expansion of a CTG trinucleotide repeat in the 3′ UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy1,2,3, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy4,5 and cardiac conduction abnormalities6, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7,8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a β-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.

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Acknowledgements

We thank H. Sarnat for review of the skeletal muscle histology; M. Tallquist for valued advice; and C. Ganders and J. Ilano for technical assistance. This work was supported by NIAMS AR45203 to S.J.T., NEI EY04542 to J.I.C, HD 24875 and HD 25326 to P.S., and a Poncin Scholarship to T.R.K.

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Correspondence to Stephen J. Tapscott.

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Further reading

Figure 1: Six5 targeting.
Figure 2: Developmental expression of Six5, as reflected by expression of the integrated β-galactosidase reporter driven from the endogenous Six5 promoter.
Figure 3: Analysis of gene expression in adult Six5-mutant mice.
Figure 4: Cataract development in Six5-deficient mice.