A murine model for human sepiapterin-reductase deficiency

Am J Hum Genet. 2006 Apr;78(4):575-87. doi: 10.1086/501372. Epub 2006 Jan 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / deficiency
  • Alcohol Oxidoreductases / genetics*
  • Animals
  • Base Sequence
  • Biopterin / analogs & derivatives
  • Biopterin / biosynthesis
  • Catecholamines / biosynthesis
  • DNA Primers
  • Disease Models, Animal*
  • Growth
  • Humans
  • Immunohistochemistry
  • Locomotion
  • Metabolism, Inborn Errors / genetics*
  • Mice
  • Mice, Knockout
  • Phenotype
  • Phenylalanine / metabolism
  • Serotonin / biosynthesis


  • Catecholamines
  • DNA Primers
  • Biopterin
  • Serotonin
  • Phenylalanine
  • Alcohol Oxidoreductases
  • sepiapterin reductase
  • sapropterin