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Dominant negative mutations in the insulin gene are the second most commoncause of permanent neonatal diabetes. However, variation in severity andpenetrance of neonatal diabetes, as in other complex genetic diseases, cannotbe accounted for by known disease mutations. In a novel approach to thisproblem, we have utilized the genetic tools available in Drosophila to modelthe effects of the C96Y mutation, a cysteine to tyrosine mutation in theinsulin protein that can cause permanent neonatal diabetes in humans. Thismutation, which disrupts a disulfide bridge in the proinsulin molecule, hasbeen shown to lead to partial protein unfolding and aggregation in theendoplasmic reticulum. It is thought to induce beta cell death in humans andmice through endoplasmic reticulum stress-mediated apoptosis. We employed theUAS/GAL4 system to create a stable fly laboratory stock expressing humaninsulin with the C96Y mutation (INSC96Y) in the Drosophila eye. We crossedthese transgenic INSC96Y flies to 36 isogenic lines derived from a wildpopulation. The F1 flies displayed a disrupted eye development phenotype, withboth reduced eye size and irregularity in ommatidia, which varied between linesand with sex. By backcrossing F1 offspring to their wild parents, we were ableto analyze the effects of naturally occurring genetic variation on the INSC96Yphenotype in flies both heterozygous and homozygous for wild third chromosomes.We observed significant differences between lines in terms of eye size, eyeshape, the presence or absence of lesions, and degree of ommatidial structurepresent, indicating that an approach that takes into account quantitativevariation in the genetic background can yield valuable insights into thephenotypic severity and penetrance of a complex genetic disease.

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