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Author Notes:

Author for correspondence: Judith L. Fridovich-Keil (jfridov@emory.edu).

J.M.I.D. conducted most of the experiments presented and participated in writing and editing the manuscript.

P.P.J.-L. contributed to this project in its early stages and also participated in editing the manuscript.

M.L.H. contributed to this project in its early stages and also participated in editing the manuscript.

K.R.G. created both the GALKexc9 and GALKRNAi(40A1) alleles and participated in editing the manuscript.

E.L.R. contributed to this project in its early stages and also participated in editing the manuscript.

J.L.F.-K. conceived of this project, coordinated the activities of the other authors, finalized the figures and wrote most of the manuscript.

We are grateful to members of the Fridovich-Keil, Moberg, and Sanyal laboratories at Emory University for many helpful discussions, to Jewels (Chhay) Bishop for contributions to creation of the GALKRNAi allele, and to Darwin Hang for assistance with mapping the breakpoints of the dGALKexc9 deletion.

The authors declare no competing or financial interests.

Subjects:

Research Funding:

This work was supported in part by the National Institutes of Health (grant numbers DK046403, DK107900 to J.L.F.-K.); and in part by institutional funds from Emory University School of Medicine (to J.L.F.-K.).

K.R.G. was supported in part by a postdoctoral fellowship from the National Institutes of Health (DK074297), and J.M.I.D. and E.L.R. were each supported in part by two training grants from the National Institutes of Health (T32MH087977 and T32GM008490).

Finally, M.L.H. was supported in part by a Diversity Supplement from the National Institutes of Health (NIDDK).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Pathology
  • Galactosemia
  • Drosophila
  • Gal-1P
  • Galactose

Acute and long-term outcomes in a Drosophila melanogaster model of classic galactosemia occur independently of galactose-1-phosphate accumulation

Tools:

Journal Title:

Disease Models and Mechanisms

Volume:

Volume 9, Number 11

Publisher:

, Pages 1375-1382

Type of Work:

Article | Final Publisher PDF

Abstract:

Classic galactosemia (CG) is a potentially lethal inborn error of metabolism that results from the profound loss of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Neonatal detection and dietary restriction of galactose minimizes or resolves the acute sequelae of CG, but fails to prevent the long-term complications experienced by a majority of patients. One of the substrates of GALT, galactose-1-phosphate (Gal-1P), accumulates to high levels in affected infants, especially following milk exposure, and has been proposedasthe key mediator of acute and long-term pathophysiology in CG. However, studies of treated patients demonstrate no association between red blood cell Gal-1P level and long-term outcome severity. Here, we used genetic, epigenetic and environmental manipulations of a Drosophila melanogaster model of CG to test the role of Gal-1P as acandidate mediator of outcome in GALT deficiency. Specifically, we both deleted and knocked down the gene encoding galactokinase (GALK) in control and GALT-null Drosophila, and assessed the acute and long-term outcomes of the resulting animals in the presence and absence of dietary galactose. GALK is the first enzyme in the Leloir pathway of galactose metabolism and is responsible for generating Gal-1P in humans and Drosophila. Our data confirmed that, as expected, loss of GALK lowered or eliminated Gal-1P accumulation in GALT-null animals. However, we saw no concomitant rescue of larval survival or adult climbing or fecundity phenotypes. Instead, we saw that loss of GALK itself was not benign and in some cases phenocopied or exacerbated the outcome seen in GALT-null animals. These findings strongly contradict the long-standing hypothesis that Gal-1P alone underlies pathophysiology of acute and long-term outcomes in GALT-null Drosophila and suggests that other metabolite(s) of galactose, and/or other pathogenic factors, might be involved.

Copyright information:

© 2016. Published by The Company of Biologists Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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