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Human Molecular Genetics Advance Access originally published online on April 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 12 1249-1255
DOI: 10.1093/hmg/ddh136
Human Molecular Genetics, Vol. 13, No. 12 © Oxford University Press 2004; all rights reserved

Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli

Günter Schwarz1,{dagger}, José Angel Santamaria-Araujo1,{dagger}, Stefan Wolf2, Heon-Jin Lee2, Ibrahim M. Adham2, Hermann-Josef Gröne3, Herbert Schwegler4, Jörn Oliver Sass5, Tanja Otte1, Petra Hänzelmann1, Ralf R. Mendel1, Wolfgang Engel2 and Jochen Reiss2,*

1Institut für Pflanzenbiologie der Technischen Universität Braunschweig, Germany, 2Institut für Humangenetik der Universitätskliniken Göttingen, Germany. 3Abteilung Zelluläre und Molekulare Pathologie, Deutsches Krebsforschungszentrum Heidelberg, Germany, 4Institut für Anatomie, Universität Magdeburg, Germany and 5Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Freiburg, Germany

Received February 13, 2004; Revised March 31, 2004; Accepted April 6, 2004

Substitution therapies for orphan genetic diseases, including enzyme replacement methods, are frequently hampered by the limited availability of the required therapeutic substance. We describe the isolation of a pterin intermediate from bacteria that was successfully used for the therapy of a hitherto incurable and lethal disease. Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder characterized by the loss of the molybdenum-dependent enzymes sulphite oxidase, xanthine oxidoreductase and aldehyde oxidase due to mutations in Moco biosynthesis genes. An intermediate of this pathway—‘precursor Z’—is more stable than the cofactor itself and has an identical structure in all phyla. Thus, it was overproduced in the bacterium Escherichia coli, purified and used to inject precursor Z-deficient knockout mice that display a phenotype which resembles that of the human deficiency state. Precursor Z-substituted mice reach adulthood and fertility. Biochemical analyses further suggest that the described treatment can lead to the alleviation of most symptoms associated with human Moco deficiency.

* To whom correspondence should be addressed at: Institut für Humangenetik der Universität Göttingen, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany. Tel: +49 5513912926; Fax: +49 551399303; Email: jreiss{at}gwdg.de


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