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Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.
T R Klesert1, D H Cho, J I Clark
1Program in Developmental Biology and Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Nature Genetics
|May 10, 2000
Summary
Myotonic dystrophy (DM1) involves CTG repeat expansion. SIX5 gene deficiency contributes to DM1 cataracts, suggesting DM1 is a multigenic disorder.
Area of Science:
- Genetics
- Molecular Biology
- Disease Mechanisms
Background:
- Myotonic dystrophy (DM1) is caused by CTG repeat expansion in the DMPK gene.
- Previous mouse models lacking DMPK orthologue (Dm15) showed some DM1 features but lacked myotonia and cataracts.
- Repeat expansion is known to reduce SIX5 gene expression.
Purpose of the Study:
- To investigate the role of SIX5 deficiency in the myotonic dystrophy phenotype.
- To determine if SIX5 haploinsufficiency contributes to DM1-associated cataracts.
Main Methods:
- Disruption of the mouse Six5 gene by replacing its first exon with a reporter gene.
- Analysis of Six5-mutant mice for reporter gene expression and phenotypic abnormalities.
- Comparison of lenticular and skeletal muscle phenotypes between mutant and control mice.
Main Results:
- Six5-mutant mice exhibited reporter expression in various tissues, including the eye lens.
- Homozygous Six5-mutant mice showed no skeletal muscle dysfunction.
- A higher incidence of lenticular opacities was observed in homozygous Six5-mutant mice compared to controls.
Conclusions:
- SIX5 deficiency plays a role in the development of cataracts in myotonic dystrophy.
- Myotonic dystrophy is likely a multigenic disorder, with SIX5 contributing to specific phenotypes.