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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 the DM1 locus on chromosome 19 causes myotonic dystrophy, 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 myopathy and cardiac conduction abnormalities, 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 beta-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.

Pubmed ID: 10802667

Authors

  • Klesert TR
  • Cho DH
  • Clark JI
  • Maylie J
  • Adelman J
  • Snider L
  • Yuen EC
  • Soriano P
  • Tapscott SJ

Journal

Nature genetics

Publication Data

May 12, 2000

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR45203
  • Agency: NEI NIH HHS, Id: EY04542
  • Agency: NICHD NIH HHS, Id: HD 24875

Mesh Terms

  • 3' Untranslated Regions
  • Animals
  • Cataract
  • Exons
  • Gene Targeting
  • Homeodomain Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myotonic Dystrophy
  • Myotonin-Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Trinucleotide Repeat Expansion