Molecular Genetics and Metabolism 85 (2005) 12–20 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.01.008 The pathogenesis of molybdenum cofactor deWciency, its delay by maternal clearance, and its expression pattern in microarray analysis Jochen Reiss a,¤ , Michael Bonin b , Herbert Schwegler c , Jörn Oliver Sass d , Enrico Garattini e , Silke Wagner a , Heon-Jin Lee a , Wolfgang Engel a , Olaf Riess b , Günter Schwarz f a Institut für Humangenetik der Universität Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany b Institut für Anthropologie und Humangenetik, Abteilung Medizinische Genetik, Tübingen, Germany c Institut für Anatomie, Universität Magdeburg, Germany d Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum, Freiburg, Germany e Istituto di Ricerche Farmacologiche, “Mario Negri”, Milano, Italy f Institut für PXanzenbiologie der Technischen Universität Braunschweig, Germany Received 21 September 2004; received in revised form 28 January 2005; accepted 28 January 2005 Available online 9 March 2005 Abstract Molybdenum cofactor (Moco)-deWciency is a lethal autosomal recessive disease, for which until now no eVective therapy is avail- able. The biochemical hallmark of this disorder is the inactivity of the Moco-dependent sulWte oxidase, which results in elevated sul- Wte and diminished sulfate levels throughout the organism. In humans, Moco-deWciency results in neurological damage, which is apparent in untreatable seizures and various brain dysmorphisms. We have recently described a murine model for Moco-deWciency, which reXects all enzyme and metabolite changes observed in the patients, and an eYcient therapy using a biosynthetic precursor of Moco has been established in this animal model. We now analyzed these mice in detail and excluded morphological brain damage, while expression analysis with microarrays indicates a massive cell death program. This neuronal damage appears to be triggered by elevated sulWte levels and is ameliorated in aVected embryos by maternal clearance.  2005 Elsevier Inc. All rights reserved. Keywords: Molybdenum; Cofactor; MOCS1; Maternal clearance; SulWte Introduction In mammals, the activity of all molybdenum-contain- ing enzymes requires a universal molybdenum cofactor (Moco) 1 [1]. This cofactor is found in sulWte oxidase, xanthine oxidoreductase, in aldehyde oxidase, and related enzymes [2]. In humans, an isolated aldehyde oxi- dase deWciency is not known, probably because of a redundancy in speciWcity with other enzymes such as xanthine oxidoreductases [3]. Mutations in the gene for xanthine oxidoreductase in most cases are asymptomatic and only a minority of patients suVers from the rela- tively mild symptoms of classical xanthinuria [4]. In con- trast, isolated sulWte oxidase deWciency results in a severe and lethal phenotype, which clinically is indistinguish- able from that of a combined Moco deWciency [3] with the pleiotropic loss of all Mo-enzyme activities. Although the absence of sulWte oxidase activity clearly is the primary cause for severe neurological dam- age and death in Moco-deWcient patients, these symp- toms could be caused (i) by sulWte toxicity, (ii) by sulfate deWciency or (iii) by a combination of both [3,5]. Dimin- ished sulfate levels could lead to reduced concentrations ¤ Corresponding author. Fax: +49 551 39903. E-mail address: jreiss@gwdg.de (J. Reiss). 1 Abbreviations used: Moco, molybdenum cofactor; Dpc, Days past coitum; Mo, molybdenum.