Mouse model for human sepiapterin reductase deficiency

Abstract

Tetrahydrobiopterin $(BH_4)$ is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, phenylalanine-4-hydroxylase, tryptophan-5-hydroxylase, tyrosine-3-hydroxylase, and glyceryl-ether mono-oxygenase. Therefore, a proper level of $BH_4$ is necessary for controlling the level of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. $BH_4$ deficiency has been shown to be closely associated with diverse neurological disorders, including pediatric neurotransmitter disorders, hyperphenylalaninemia, depression, autism, Parkinson’s disease, and dopamine-responsive dystonia (Segawa’s disease), to name a few. Sepiapterin reductase (SR) is an enzyme that catalyzes the final step of $BH_4$ biosynthesis. While the number of cases of neurological disorders resulting from deficiencies of other catalytic enzymes involved in $BH_4$ biosynthesis and metabolism has been accumulating, only a handful of cases of SR deficiency have been reported, and the role of SR in $BH_4$ biosynthesis in vivo has been poorly understood. Here, I report that the homeostasis of $BH_4$, dopamine, Norepinephrine, serotonin, and phenylalanine are greatly disturbed in $Spr^{-/-}$ mice, which exhibited 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 SR deficiency patients.