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Neomorphic agouti mutations in obese yellow mice
D M Duhl1, H Vrieling, K A Miller
1Department of Pediatrics, Stanford School of Medicine, California 94305.
Nature Genetics
|September 1, 1994
Summary
Several mouse agouti gene mutations cause obesity and yellow coats. These mutations, including Ay, Aiy, Asy, and Avy, result from deletions or intracisternal A particle insertions, leading to altered gene expression and disease phenotypes.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- The mouse agouti gene controls coat color and has pleiotropic effects, including obesity.
- Dominant mutations in the agouti gene are associated with obesity and a yellow coat phenotype.
- The Ay allele is a large deletion affecting multiple contiguous genes.
Purpose of the Study:
- To investigate the molecular basis of three obesity-associated agouti mutations: Aiy, Asy, and Avy.
- To understand how these mutations lead to ubiquitous expression of a chimaeric RNA encoding normal agouti protein.
- To establish a model for allele-specific imprinting and disease phenotypes.
Main Methods:
- Molecular analysis of agouti mutations.
- Identification of intracisternal A particle (IAP) element insertions.
- RNA expression analysis.
Main Results:
- Three obesity-associated agouti mutations (Aiy, Asy, Avy) result from distinct molecular alterations.
- The Aiy and Avy alleles are caused by IAP element insertions upstream of agouti coding sequences.
- These insertions lead to ubiquitous expression of a chimaeric RNA encoding a normal agouti protein.
Conclusions:
- The study provides a molecular model for allele-specific imprinting.
- Mechanisms activating proto-oncogenes can also cause other disease phenotypes.
- Understanding agouti mutations sheds light on gene regulation and disease development.