Dwarfism and Low Insulin-like Growth Factor-1 Due to Dopamine Depletion in Pts–/– Mice Rescued by Feeding Neurotransmitter Precursors and H4-biopterin

• Published in: The Journal of biological chemistry Vol. 278; no. 30; pp. 28303 - 28311
• Main Authors: Elzaouk, Lina, Leimbacher, Walter, Turri, Matteo, Ledermann, Birgit, Bürki, Kurt, Blau, Nenad, Thöny, Beat
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2003
• Subjects: 5-Hydroxytryptophan - pharmacology; Animals; Biopterins - analogs & derivatives; Biopterins - chemistry; Biopterins - metabolism; Body Weight; Cell Division; Dopamine - metabolism; Dwarfism - genetics; Gene Deletion; Genetic Vectors; Genotype; Heterozygote; Homozygote; Insulin-Like Growth Factor I - metabolism; Kinetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurotransmitter Agents; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Phenotype; Phosphorus-Oxygen Lyases - genetics; Phosphorus-Oxygen Lyases - metabolism; Phosphorus-Oxygen Lyases - physiology; Polymerase Chain Reaction; Thyroxine - blood; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M303986200

The tetrahydrobiopterin (BH4) cofactor is essential for the biosynthesis of catecholamines and serotonin and for nitric-oxide synthase (NOS). Alterations in BH4 metabolism are observed in various neurological and psychiatric diseases, and mutations in one of the human metabolic genes causes hyperphenylalaninemia and/or monoamine neurotransmitter deficiency. We report on a knockout mouse for the Pts gene, which codes for a BH4-biosynthetic enzyme. Homozygous Pts–/– mice developed with normal morphology but died after birth. Upon daily oral administration of BH4 and neurotransmitter precursors the Pts–/– mice eventually survived. However, at sexual maturity (6 weeks) the mice had only one-third of the normal body weight and were sexually immature. Biochemical analysis revealed no hyperphenylalaninemia, normal brain NOS activity, and almost normal serotonin levels, but brain dopamine was 3% of normal. Low dopamine leads to impaired food consumption as reflected by the severe growth deficiency and a 7-fold reduced serum insulin-like growth factor-1 (IGF-1). This is the first link shown between 6-pyruvoyltetrahydropterin synthase- or BH4-biosynthetic activity and IGF-1.