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Author Notes:

Author for correspondence (jfridov@emory.edu)

R.D.S. created all of the dGALE excision alleles used in this work and also generated all of the data presented in Figs 2–5

J.M.I.S. and R.D.S. collaborated to generate the data for Tables 1 and ​and 2

K.H.M. provided general oversight for experiments involving fly genetic manipulation

J.L.F.-K. conceived the project and provided oversight for much of its completion

R.D.S. and J.L.F.-K. wrote the manuscript with editorial assistance from J.M.I.S. and K.H.M.

We thank Kerry Garza, Elisa Margolis and the members of the Moberg and Sanyal labs for helpful discussions concerning this project; Emily Ryan for help with statistical analyses; Michael Santoro for assistance with mapping of UAS-hGALE insertions; Jewels Chhay for contributions to the creation of the UAS-hGALE construct; and Doug Rennie for embryo injection of the hGALE transgene.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health grant DK046403 (to J.L.F.-K. and K.H.M.).

UDP-galactose 4′ epimerase (GALE) is essential for development of Drosophila melanogaster

Tools:

Journal Title:

Disease Models and Mechanisms

Volume:

Volume 3, Number 9-10

Publisher:

, Pages 628-638

Type of Work:

Article | Final Publisher PDF

Abstract:

SUMMARY UDP-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.

Copyright information:

© 2010

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