Profound impairment of galactose-1-phosphate uridylyltransferase (GALT) results in the inborn error of metabolism known as classic galactosemia. Although the acute and potentially lethal sequelae of this disorder can be resolved or prevented by early detection and lifelong dietary restriction of galactose, many treated patients nevertheless go on to experience serious long-term complications, including cognitive disabilities and speech/language disorders in nearly half of all patients, and primary or premature ovarian failure in close to 85% of female patients. Despite more than 50 years of investigation, the mechanisms underlying the pathophysiology of galactosemia remain unclear, and animal models of the disease have failed to recapitulate the patient phenotype, further complicating studies. The long-term goal of our proposed research is to define the biochemical bases of this pathophysiology, thereby enabling development of novel and more effective treatments for patients with galactosemia. Our short-term objective is to define the roles of specific biochemical factors, including aberrant glycosylation, as potential mediators of galactose sensitivity in GALT- and/or GALE-impaired yeast and mammalian cells. We further propose to test the roles of these same candidate factors as potential mediators of outcome in a large cohort of patients with classic galactosemia.
Our Specific Aims are: (1) to define the roles of GALK, GALE, and UGP1 as candidate modifiers of galactose sensitivity in yeast and human cell model systems of galactosemia, (2) to define the nature and underlying cause(s) of aberrant glycosylation in fibroblasts from patients with classic galactosemia and generalized epimerase-deficiency galactosemia, and (3) to define biochemical modifiers of patient outcomes in a cohort of classic galactosemia patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-B (02))
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Mckeon, Catherine T
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Emory University
Schools of Medicine
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Shaw, Kelly A; Mulle, Jennifer G; Epstein, Michael P et al. (2017) Gastrointestinal Health in Classic Galactosemia. JIMD Rep 33:27-32
Tran, Thanh-Thanh Claire V; Liu, Ying; Zwick, Michael E et al. (2015) A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia. JIMD Rep 19:1-6
Liu, Ying; Sidhu, Alpa; Bean, Lora H et al. (2015) Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia. Clin Chim Acta 446:171-4
Li, Yijun; Huang, Xiaoping; Harmonay, Lauren et al. (2014) Liquid chromatography-tandem mass spectrometry enzyme assay for UDP-galactose 4'-epimerase: use of fragment intensity ratio in differentiation of structural isomers. Clin Chem 60:783-90
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Liu, Ying; Bentler, Kristi; Coffee, Bradford et al. (2013) A Case Study of Monozygotic Twins Apparently Homozygous for a Novel Variant of UDP-Galactose 4'-epimerase (GALE) : A Complex Case of Variant GALE. JIMD Rep 7:89-98
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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
Liu, Ying; Xia, Baoyun; Gleason, Tyler J et al. (2012) N- and O-linked glycosylation of total plasma glycoproteins in galactosemia. Mol Genet Metab 106:442-54

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