One of the fundamental questions in human genetics concerns the normal function of proteins associated with genetic disease, and the impact of patient mutations on those proteins and their activities. The long-term goal of this project is to elucidate the natural structure/ function relationships and interactions of enzymes that mediate galactose metabolism in humans, and the impact of mutations in the corresponding genes that result in galactosemia, a potentially lethal inborn error of metabolism that affects - 1145,000 liveborns. Galactosemia is characterized by extraordinary allelic, biochemical, and clinical heterogeneity. The proposed experiments address the basis of that heterogeneity, and focus on galactose- 1-phosphate uridylyltransferase (GALT), impaired in patients with classic galactosemia, and UDP-galactose-4'-epimerase (GALE), impaired in patients with epimerase-deficiency galactosemia. These enzymes normally catalyze successive steps in the Leloir pathway of galactose metabolism. Human GALE further catalyzes the interconversion of UDP-gaINAc/UDPglcNAc, thereby regulating substrate pools essential for all 0-linked glycosylation reactions in humans. Prior studies have demonstrated marked allelic heterogeneity in both galactosemias, and have suggested a relationship between genotype, biochemical impairment, and clinical outcome for both disorders. The basis for why some mutations or allelic combinations result in greater impairment than others, however, remains largely obscure, and is a principle focus for the proposed work. The short-term goals of this project are to: (1) define structure/function relationships and interactions for both wild-type and mutant forms of human GALT, (2) define structure/function relationships and interactions for both wild-type and mutant forms of human GALE, and (3) define the role of human GALE in determining metabolic and glycosylation defects in mammalian cells with transferase-deficiency vs. epimerase-deficiency galactosemia. The results of these studies will be significant in that they will provide basic science advances and challenge existing paradigms regarding human GALT and GALE activities, structures, interactions, coordination, and metabolic influence. They will also result in the production of useful reagents, including mammalian cell lines specifically deficient in 0-linked protein glycosylation. Finally, they will offer improved diagnostic and prognostic tools for both classic and epimerase-deficiency galactosemia, and ultimately should help to inform a rational approach to the generation of novel treatments for patients with these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK046403-10
Application #
6542873
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
1993-08-01
Project End
2007-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
10
Fiscal Year
2002
Total Cost
$351,500
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Frederick, Allison B; Cutler, David J; Fridovich-Keil, Judith L (2017) Rigor of non-dairy galactose restriction in early childhood, measured by retrospective survey, does not associate with severity of five long-term outcomes quantified in 231 children and adults with classic galactosemia. J Inherit Metab Dis 40:813-821
Daenzer, Jennifer M I; Jumbo-Lucioni, Patricia P; Hopson, Marquise L et al. (2016) Acute and long-term outcomes in a Drosophila melanogaster model of classic galactosemia occur independently of galactose-1-phosphate accumulation. Dis Model Mech 9:1375-1382
Jumbo-Lucioni, Patricia P; Ryan, Emily L; Hopson, Marquise L et al. (2014) Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia. Antioxid Redox Signal 20:2361-71
Jumbo-Lucioni, Patricia P; Hopson, Marquise L; Hang, Darwin et al. (2013) Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia. Dis Model Mech 6:84-94
Spencer, Jessica B; Badik, Jennifer R; Ryan, Emily L et al. (2013) Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab 98:E1257-65
Ryan, Emily L; Lynch, Mary Ellen; Taddeo, Elles et al. (2013) Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia. J Inherit Metab Dis 36:1049-61
Daenzer, Jennifer M I; Sanders, Rebecca D; Hang, Darwin et al. (2012) UDP-galactose 4'-epimerase activities toward UDP-Gal and UDP-GalNAc play different roles in the development of Drosophila melanogaster. PLoS Genet 8:e1002721
Ryan, Emily L; DuBoff, Brian; Feany, Mel B et al. (2012) Mediators of a long-term movement abnormality in a Drosophila melanogaster model of classic galactosemia. Dis Model Mech 5:796-803
McCorvie, Thomas J; Wasilenko, Jamie; Liu, Ying et al. (2011) In vivo and in vitro function of human UDP-galactose 4'-epimerase variants. Biochimie 93:1747-54
Sanders, Rebecca D; Sefton, Jennifer M I; Moberg, Kenneth H et al. (2010) UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster. Dis Model Mech 3:628-38

Showing the most recent 10 out of 15 publications