Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy

Expansion of a CTG trinucleotide repeat in the 3' UTR of the gene DMPK at t he DM1 locus on chromosome 19 causes myotonic dystrophy(1-3), a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mo use orthologue of human DMPK, produced mice with a mild myopathy(4,5) and c ardiac conduction abnormalities(6), but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrate d that repeat expansion decreases expression of the adjacent gene SIX5 (ref s 7,8), which encodes a homeodomain transcription factor, To determine whet her SIX5 deficiency contributes to the myotonic dystrophy phenotype, we dis rupted mouse Six5 by replacing the first exon with a beta-galactosidase rep orter. Six5-mutant mice showed reporter expression in multiple tissues, inc luding the developing lens. Homozygous mutant mice had no apparent abnormal ities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contrib utes to the cataract phenotype in myotonic dystrophy, and that myotonic dys trophy represents a multigenic disorder.