title: Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.
abstract: 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.
authors.affiliation: Program in Developmental Biology and Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Klesert
authors.forename: D H
authors.initials: DH
authors.lastname: Cho
authors.forename: J I
authors.initials: JI
authors.lastname: Clark
authors.forename: J
authors.initials: J
authors.lastname: Maylie
authors.forename: J
authors.initials: J
authors.lastname: Adelman
authors.forename: L
authors.initials: L
authors.lastname: Snider
authors.forename: E C
authors.initials: EC
authors.lastname: Yuen
authors.forename: P
authors.initials: P
authors.lastname: Soriano
authors.forename: S J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002386:Cataract / Q000201:enzymology / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009223:Myotonic Dystrophy / Q000201:enzymology / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C585517:DMPK protein, human; C585516:DMPK protein, mouse; D018398:Homeodomain Proteins; C486344:Six5 protein, mouse; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases