Naturally Occurring Genetic Variation Influences the Severity of Drosophila Eye Degeneration Induced by Expression of a Mutant Human Insulin Gene

Dominant negative mutations in the insulin gene are the second most common cause of permanent neonatal diabetes. However, variation in severity and penetrance of neonatal diabetes, as in other complex genetic diseases, cannot be accounted for by known “disease” mutations. In a novel approach to this problem, we have utilized the genetic tools available in Drosophila to model the effects of the C96Y mutation, a cysteine to tyrosine mutation in the insulin protein that can cause permanent neonatal diabetes in humans. This mutation, which disrupts a disulfide bridge in the proinsulin molecule, has been shown to lead to partial protein unfolding and aggregation in the