A Drosophila melanogaster model of classic galactosemia.
Classic 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.
Kushner
Rebekah F
RF
Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA 30322, USA.
Ryan
Emily L
EL
Sefton
Jennifer M I
JM
Sanders
Rebecca D
RD
Lucioni
Patricia Jumbo
PJ
Moberg
Kenneth H
KH
Fridovich-Keil
Judith L
JL
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism / Q000494:pharmacology; D005693:Galactosemias / Q000201:enzymology / Q000473:pathology*; D005695:Galactosephosphates / Q000378:metabolism; D018522:Gravitropism / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000378:metabolism
D029721:Drosophila Proteins; D005695:Galactosephosphates; C029973:galactose-1-phosphate; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase; D005690:Galactose