Environmental and genetic modifiers of Shudderer, a Drosophila voltage-gated sodium channel mutant

There is a complex relationship between genetic mutations and their phenotypic expression. Two patients who carry the exactly same disease-causing mutation can have drastically different severity in disease symptoms. Such phenotypic variations may be due to environmental factors, such as diet, stress and temperature, as well as genetic variations, including single nucleotide polymorphisms and copy number variations in other loci. From a clinical point of view, the environmental and genetic factors that modify phenotypic severity are important because, even when we cannot correct the original mutations, it may be able to reduce the burden of genetically inherited disorders by manipulating these modifiers. To study environmental and genetic modifiers, we used Shudderer (Shu), a Drosophila mutant for the voltage-gated sodium (Na_v) channel gene, as an experimental model. Na_v channels are essential for generation and propagation of action potentials in neurons. Reflecting their functional importance in neural function, mutations in the Na_v channel genes are associated with a variety of human neurological disorders. Shu mutants display severe behavioral defects (e.g., spontaneous jerking and heat-induced seizures) and morphological abnormalities (e.g., indented thorax and down-turned wings). The goal of this study was to identify and characterize the environmental and genetic factors that modify behavioral and morphological phenotypes of Shu mutants. For environmental modifiers, we serendipitously discovered that a diet supplemented with milk dramatically reduces the Shu phenotypes. To identify genetic modifiers, we took two independent approaches, microarray analysis and unbiased forward genetic modifier screening. We found that reduction of Gadd45 or GstS1 activity leads to suppression of the Shu phenotypes to different degrees. Intriguingly, the effects of these genetic and environmental modifiers apparently converge into enhancement of the GABAergic inhibitory system. Because the molecular and cellular mechanisms underlying the basic neurobiological processes are highly conserved between flies and humans, our findings are expected to provide fundamental insights into genetic and environmental modifiers for human Na_v channel gene mutations, leading to the future development of novel strategies for preventing and treating disorders caused by dysfunctional Na_vchannels.