SUMMARYUDP-galactose 4' epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose in the final step of the Leloir pathway; human GALE (hGALE) also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. GALE therefore plays key roles in the metabolism of dietary galactose, in the production of endogenous galactose, and in maintaining the ratios of key substrates for glycoprotein and glycolipid biosynthesis. Partial impairment of hGALE results in the potentially lethal disorder epimerase-deficiency galactosemia. We report here the generation and initial characterization of a first whole-animal model of GALE deficiency using the fruit fly Drosophila melanogaster. Our results confirm that GALE function is essential in developing animals; Drosophila lacking GALE die as embryos but are rescued by the expression of a human GALE transgene. Larvae in which GALE has been conditionally knocked down die within days of GALE loss. Conditional knockdown and transgene expression studies further demonstrate that GALE expression in the gut primordium and Malpighian tubules is both necessary and sufficient for survival. Finally, like patients with generalized epimerase deficiency galactosemia, Drosophila with partial GALE loss survive in the absence of galactose but succumb in development if exposed to dietary galactose. These data establish the utility of the fly model of GALE deficiency and set the stage for future studies to define the mechanism(s) and modifiers of outcome in epimerase deficiency galactosemia.

SUMMARYClassic galactosemia is a potentially lethal disorder that results from profound impairment of galactose-1-phosphate uridylyltransferase (GALT). Despite decades of research, the underlying pathophysiology of classic galactosemia remains unclear, in part owing to the lack of an appropriate animal model. Here, we report the establishment of a Drosophila melanogaster model of classic galactosemia; this is the first whole-animal genetic model to mimic aspects of the patient phenotype. Analogous to humans, GALT-deficient D. melanogaster survive under conditions of galactose restriction, but accumulate elevated levels of galactose-1-phosphate and succumb during larval development following galactose exposure. As in patients, the potentially lethal damage is reversible if dietary galactose restriction is initiated early in life. GALT-deficient Drosophila also exhibit locomotor complications despite dietary galactose restriction, and both the acute and long-term complications can be rescued by transgenic expression of human GALT. Using this new Drosophila model, we have begun to dissect the timing, extent and mechanism(s) of galactose sensitivity in the absence of GALT activity.