A Murine Model for Human Sepiapterin-Reductase Deficiency

• Published in: American journal of human genetics 2006-04, Vol.78 (4), p.575-587
• Main Authors: Yang, Seungkyoung, Lee, Young Jae, Kim, Jin-Man, Park, Sean, Peris, Joanna, Laipis, Philip, Park, Young Shik, Chung, Jae Hoon, Oh, S. Paul
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - deficiency; Alcohol Oxidoreductases - genetics; Animals; Base Sequence; Biological and medical sciences; Biopterins - analogs & derivatives; Biopterins - biosynthesis; Catecholamines - biosynthesis; Disease Models, Animal; DNA Primers; Enzymes; General aspects. Genetic counseling; Genes; Growth; Humans; Immunohistochemistry; Locomotion; Medical genetics; Medical sciences; Metabolism, Inborn Errors - genetics; Mice; Mice, Knockout; Molecular biology; Nitric oxide; Patients; Phenotype; Phenylalanine - metabolism; Serotonin - biosynthesis
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/501372

Tetrahydrobiopterin (BH 4) 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 BH 4 is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH 4 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 BH 4 biosynthesis. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in BH 4 biosynthesis and metabolism has been increasing, only a handful of cases of SPR deficiency have been reported, and the role of SPR in BH 4 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 BH 4 and for the normal functions of BH 4-dependent enzymes. The Spr −/− mice exhibit phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH 4 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 BH 4 deficiencies.