Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 78, Issue 4, 575-587, 1 April 2006
doi:10.1086/501372
A Murine Model for Human Sepiapterin-Reductase Deficiency
Seungkyoung Yang1, 3, *, Young Jae Lee3, *, Jin-Man Kim2, Sean Park3, Joanna Peris5, Philip Laipis4, Young Shik Park6, Jae Hoon Chung1 and S. Paul Oh3, 
, 
1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
2 Department of Pathology, Chungnam National University School of Medicine, Daejeon, South Korea
3 Departments of Physiology and Functional Genomics University of Florida College of Pharmacy, Gainesville
4 Biochemistry and Molecular Biology, University of Florida College of Medicine
5 Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville
6 School of Biotechnology and Biomedical Science, Inje University, Kimhae, South Korea
Address for correspondence and reprints: Dr. S. Paul Oh, Department of Physiology and Functional Genomics, University of Florida, 1600 SW Archer Road, Room D533d, Gainesville, FL 32610* These two authors contributed equally to this work.
Abstract
Tetrahydrobiopterin (BH4) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH4 is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH4 deficiency has been shown to be closely associated with diverse neurological psychiatric disorders. Sepiapterin reductase (SPR) is an enzyme that catalyzes the final step of BH4 biosynthesis. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in BH4 biosynthesis and metabolism has been increasing, only a handful of cases of SPR deficiency have been reported, and the role of SPR in BH4 biosynthesis in vivo has been poorly understood. Here, we report that mice deficient in the Spr gene (Spr−/−) display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH4 and for the normal functions of BH4-dependent enzymes. The Spr−/− mice exhibit phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH4 and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr−/− mice share striking similarities with the symptoms observed in SPR-deficient patients. This Spr mutant strain of mice will be an invaluable resource to elucidate many important issues regarding SPR and BH4 deficiencies.
Article Information
PubMed
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