Dwarfism and low insulin-like growth factor-1 due to dopamine depletion in Pts-/- mice rescued by feeding neurotransmitter precursors and H4-biopterin.
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.
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, Division of Animal Facility, University of Zürich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Lina
L
Elzaouk
Walter
W
Leimbacher
Matteo
M
Turri
Birgit
B
Ledermann
Kurt
K
Burki
Nenad
N
Blau
Beat
B
Thony
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D001835:Body Weight; D002455:Cell Division; D004298:Dopamine / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics*; D017353:Gene Deletion; D005822:Genetic Vectors; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010641:Phenotype; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016133:Polymerase Chain Reaction; D013974:Thyroxine / Q000097:blood; D013997:Time Factors
D018377:Neurotransmitter Agents; D001708:Biopterins; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D006916:5-Hydroxytryptophan; D019001:Nitric Oxide Synthase; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; C003402:sapropterin; D013974:Thyroxine; D004298:Dopamine