A murine model for human sepiapterin-reductase deficiency

Seungkyoung Yang, Young Jae Lee, Jin Man Kim, Sean S Park, Joanna Peris, Philip Laipis, Young Shik Park, Jae Hoon Chung, S. Paul Oh

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 BH 4 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 BH 4-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.

Original languageEnglish (US)
Pages (from-to)575-587
Number of pages13
JournalAmerican Journal of Human Genetics
Volume78
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

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sepiapterin reductase
Phenylketonurias
Dwarfism
Phenylalanine
Serotonin
Enzymes
Glyceryl Ethers
Mutant Strains Mice
Pterins
Oxygenases
Coenzymes
Mixed Function Oxygenases
Nervous System Diseases
Nitric Oxide Synthase
Catecholamines
Neurotransmitter Agents
Psychiatry
Dopamine
Norepinephrine
Nitric Oxide

ASJC Scopus subject areas

  • Genetics

Cite this

Yang, S., Lee, Y. J., Kim, J. M., Park, S. S., Peris, J., Laipis, P., ... Oh, S. P. (2006). A murine model for human sepiapterin-reductase deficiency. American Journal of Human Genetics, 78(4), 575-587. https://doi.org/10.1086/501372

A murine model for human sepiapterin-reductase deficiency. / Yang, Seungkyoung; Lee, Young Jae; Kim, Jin Man; Park, Sean S; Peris, Joanna; Laipis, Philip; Park, Young Shik; Chung, Jae Hoon; Oh, S. Paul.

In: American Journal of Human Genetics, Vol. 78, No. 4, 04.2006, p. 575-587.

Research output: Contribution to journalArticle

Yang, S, Lee, YJ, Kim, JM, Park, SS, Peris, J, Laipis, P, Park, YS, Chung, JH & Oh, SP 2006, 'A murine model for human sepiapterin-reductase deficiency', American Journal of Human Genetics, vol. 78, no. 4, pp. 575-587. https://doi.org/10.1086/501372
Yang, Seungkyoung ; Lee, Young Jae ; Kim, Jin Man ; Park, Sean S ; Peris, Joanna ; Laipis, Philip ; Park, Young Shik ; Chung, Jae Hoon ; Oh, S. Paul. / A murine model for human sepiapterin-reductase deficiency. In: American Journal of Human Genetics. 2006 ; Vol. 78, No. 4. pp. 575-587.
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