A galactose-1-phosphate uridylyltransferase-null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue-specific and longitudinal differences in galactose metabolism

• Type of Material: Article
• Authors: Shauna A. Rasmussen, Emory University; Jennifer M. I. Daenzer, Emory University; Jessica A. MacWilliams, Emory University; S. Taylor Head, Emory University; Martine B. Williams, Emory University; Aron M. Geurts, Medical College of Wisconsin; Jason Schroeder, Emory University; David Weinshenker, Emory University; Judith Fridovich-Keil, Emory University
• Language: English
• Date: 2020-05-01
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/jimd.12205
• Title of Journal or Parent Work: Journal of Inherited Metabolic Disease
• Volume: 43
• Issue: 3
• Start Page: 518
• End Page: 528
• Grant/Funding Information: This work was supported by institutional funds from Emory University School of Medicine (Department of Human Genetics) and by grants from the National Institutes of Health R01DK107900 and R21HD092785 (all to J.L.F.K.).
• Keywords: galactosemia; Science & Technology; Growth; Restriction; Endocrinology & Metabolism; Genetics & Heredity; rat; Mouse model; Life Sciences & Biomedicine; Research & Experimental Medicine; Medicine, Research & Experimental; GALT; cognitive; model; metabolite

Abstract

Classic galactosemia (CG) is a potentially lethal inborn error of metabolism, if untreated, that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the middle enzyme of the Leloir pathway of galactose metabolism. While newborn screening and rapid dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms of CG, by mid-childhood, most treated patients experience significant complications. The mechanisms underlying these long-term deficits remain unclear. Here we introduce a new GALT-null rat model of CG and demonstrate that these rats display cataracts, cognitive, motor, and growth phenotypes reminiscent of patients outcomes. We further apply the GALT-null rats to test how well blood biomarkers, typically followed in patients, reflect metabolic perturbations in other, more relevant tissues. Our results document that the relative levels of galactose metabolites seen in GALT deficiency differ widely by tissue and age, and that red blood cell Gal-1P, the marker most commonly followed in patients, shows no significant association with Gal-1P in other tissues. The work reported here establishes our outbred GALT-null rats as an effective model for at least four complications characteristic of CG, and sets the stage for future studies addressing mechanism and testing the efficacy of novel candidate interventions.