Human Molecular Genetics Advance Access published online on March 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh112
© 2004 by Oxford University Press
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1 Center for Molecular Neurobiology Hamburg (ZMNH), Institute for Neural Signal Transduction, Hamburg, Germany
* To whom correspondence should be addressed. E-mail: isbrandt{at}uni-hamburg.de.
We generated a knockout mouse model for guanidinoacetate N-methyltransferase (GAMT) deficiency (MIM 601240), the first discovered human creatine deficiency syndrome, by gene targeting in embryonic stem cells. Disruption of the open reading frame of the murine GAMT gene in the first exon resulted in the elimination of 210 of the 237 amino acids present in mGAMT. The creation of an mGAMT null allele was verified at the genetic, RNA, and protein levels. GAMT knockout mice have markedly increased guanidinoacetate (GAA) and reduced creatine and creatinine levels in brain, serum, and urine, which are key findings in human GAMT patients. In vivo 31P magnetic resonance spectroscopy showed high levels of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle, and brain. These biochemical alterations were comparable to those found in human GAMT patients and can be attributed to the very similar GAMT expression patterns found by us in human and mouse tissues. We provide evidence that GAMT deficiency in mice causes biochemical adaptations in brain and skeletal muscle. It is associated with increased neonatal mortality, muscular hypotonia, decreased male fertility, and a non-leptin-mediated life-long reduction in body weight due to reduced body fat mass. Therefore, GAMT knockout mice are a valuable creatine deficiency model for studying the effects of high-energy phosphate depletion in brain, heart, skeletal muscle, and other organs.
Article
Severely altered guanidino compound levels, disturbed body weight homeostasis, and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency
2 Laboratory of Neurochemistry & Behaviour, Born-Bunge Foundation, University of Antwerp, Belgium
3 Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
4 Department of Radiology, UMC Nijmegen, Nijmegen, The Netherlands
5 Dept. of Pediatrics, University Hospital Hamburg, Hamburg, Germany; Department of Pediatrics, University of Hanover, Germany
6 Dept. of Pediatrics, University Hospital Hamburg, Hamburg, Germany; Department of Pediatrics, University of Göttingen, Germany
7 Dept. of Anatomy, University Hospital Hamburg, Hamburg, Germany
8 Dept. of Pediatrics, University Hospital Hamburg, Hamburg, Germany
9 Zentrum für Molekulare Neurobiologie Hamburg, Institut für Neurale Signalverarbeitung, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany
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