Genetic Complexity in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin

TL;DR

This study uses Drosophila to model human neonatal diabetes caused by misfolded proinsulin, revealing genetic complexity, tissue-specific variability, and potential for GWAS analysis of disease phenotypes.

Contribution

It introduces a Drosophila model for diabetes-associated misfolded human proinsulin and characterizes its genetic and tissue-specific variability.

Findings

Mutant proinsulin causes developmental defects in fly tissues.

Endoplasmic reticulum stress response is activated by mutant proinsulin.

Disease severity varies with genetic background and tissue type.

Abstract

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.