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J. Biol. Chem., Vol. 278, Issue 30, 28303-28311, July 25, 2003

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

Lina Elzaouk , Walter Leimbacher , Matteo Turri  , Birgit Ledermann ¶, Kurt Bürki ¶, Nenad Blau  and Beat Thöny  ||

From the Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, ^¶Division of Animal Facility, University of Zürich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland

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.

Received for publication, April 16, 2003 , and in revised form, May 5, 2003.

^* This work was supported by the Rentenanstalt/Swiss Life, Stiftung für wissenschaftliche Forschung an der Universität Zürich, and the Swiss National Science Foundation (Grant 31-066953.01). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: European Patent Office, 80339 München, Germany.

^|| To whom correspondence should be addressed. Tel.: 41-1-266-7622; Fax: 41-1-266-7169; E-mail: beat.thony{at}kispi.unizh.ch.

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