  Here we use Drosophila melanogaster to create a genetic model of human
permanent neonatal diabetes mellitus and present experimental results
describing dimensions of this complexity. The approach involves the transgenic
expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a
cause of the disease. When expressed in fly imaginal discs, hINSC96Y causes a
reduction of adult structures, including the eye, wing and notum. Eye imaginal
discs exhibit defects in both the structure and arrangement of ommatidia. In
the wing, expression of hINSC96Y leads to ectopic expression of veins and
mechano-sensory organs, indicating disruption of wild type signaling processes
regulating cell fates. These readily measurable disease phenotypes are
sensitive to temperature, gene dose and sex. Mutant (but not wild type)
proinsulin expression in the eye imaginal disc induces IRE1-mediated Xbp1
alternative splicing, a signal for endoplasmic reticulum stress response
activation, and produces global change in gene expression. Mutant hINS
transgene tester strains, when crossed to stocks from the Drosophila Genetic
Reference Panel produces F1 adults with a continuous range of disease
phenotypes and large broad-sense heritability. Surprisingly, the severity of
mutant hINS-induced disease in the eye is not correlated with that in the notum
in these crosses, nor with eye reduction phenotypes caused by the expression of
two dominant eye mutants acting in two different eye development pathways, Drop
(Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue
specificity of genetic variability for mutant hINS-induced disease thus has its
own distinct signature. The genetic dominance of disease-specific phenotypic
variability makes this approach amenable to genome-wide association study
(GWAS) in a simple F1 screen of natural variation.
