Volume 43, Issue 3 pp. 518-528
ORIGINAL ARTICLE
Open Access

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

Shauna A. Rasmussen

Shauna A. Rasmussen

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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Jennifer M. I. Daenzer

Jennifer M. I. Daenzer

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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Jessica A. MacWilliams

Jessica A. MacWilliams

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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S. Taylor Head

S. Taylor Head

Rollins School of Public Health, Graduate Program in Biostatistics, Emory University, Atlanta, Georgia

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Martine B. Williams

Martine B. Williams

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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Aron M. Geurts

Aron M. Geurts

Gene Editing Rat Resource Center, Medical College of Wisconsin, Milwaukee, Wisconsin

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Jason P. Schroeder

Jason P. Schroeder

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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David Weinshenker

David Weinshenker

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

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Judith L. Fridovich-Keil

Corresponding Author

Judith L. Fridovich-Keil

Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia

Correspondence

Judith L. Fridovich-Keil, Department of Human Genetics, Emory University School of Medicine, Emory University, Rm. 325.2 Whitehead Bldg., 615 Michael St., Atlanta, GA 30322.

Email: [email protected]

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First published: 17 December 2019
Citations: 14
Shauna A. Rasmussen and Jennifer M. I. Daenzer contributed equally to this study.
Communicating Editor: Ina Knerr

Funding information: National Institutes of Health, Grant/Award Numbers: R21HD092785, R01DK107900; Emory University School of Medicine (Department of Human Genetics)

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.

CONFLICT OF INTEREST

All of the authors declare that they have no competing interests.

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