title: Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients.
abstract: Molybdenum cofactor (MoCo) deficiency is a rare, autosomal-recessive disorder, mainly caused by mutations in MOCS1 (MoCo deficiency type A) or MOCS2 (MoCo deficiency type B) genes; the absence of active MoCo results in a deficiency in all MoCo-dependent enzymes. Patients with MoCo deficiency present with neonatal seizures, feeding difficulties, severe developmental delay, brain atrophy and early childhood death. Although substitution therapy with cyclic pyranopterin monophosphate (cPMP) has been successfully used in both Mocs1 knockout mice and in patients with MoCo deficiency type A, there is currently no Mocs2 knockout mouse and no curative therapy for patients with MoCo deficiency type B. Therefore, we generated and characterized a Mocs2-null mouse model of MoCo deficiency type B. Expression analyses of Mocs2 revealed a ubiquitous expression pattern; however, at the cellular level, specific cells show prominent Mocs2 expression, e.g., neuronal cells in cortex, hippocampus and brainstem. Phenotypic analyses demonstrated that Mocs2 knockout mice failed to thrive and died within 11 days after birth. None of the tested MoCo-dependent enzymes were active in Mocs2-deficient mice, leading to elevated concentrations of purines, such as hypoxanthine and xanthine, and non-detectable levels of uric acid in the serum and urine. Moreover, elevated concentrations of S-sulfocysteine were measured in the serum and urine. Increased levels of xanthine resulted in bladder and kidney stone formation, whereas increased concentrations of toxic sulfite triggered neuronal apoptosis. In conclusion, Mocs2-deficient mice recapitulate the severe phenotype observed in humans and can now serve as a model for preclinical therapeutic approaches for MoCo deficiency type B.
authors.affiliation: Institute of Human Genetics, University Medical Center Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jakubiczka-Smorag
authors.affiliation: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zuelpicher Strasse 47, 50674, Koeln, Germany.
authors.forename: Jose Angel
authors.initials: JA
authors.lastname: Santamaria-Araujo
authors.affiliation: Institute of Neuropathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075, Goettingen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zuelpicher Strasse 47, 50674, Koeln, Germany.
authors.forename: Avadh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institute of Pathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075, Goettingen, Germany.
authors.forename: Samy
authors.initials: S
authors.lastname: Hakroush
authors.affiliation: Institute of Neuropathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075, Goettingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brueck
authors.affiliation: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zuelpicher Strasse 47, 50674, Koeln, Germany.
authors.forename: Guenter
authors.initials: G
authors.lastname: Schwarz
authors.affiliation: Institute of Human Genetics, University Medical Center Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Burfeind
authors.affiliation: Institute of Human Genetics, University Medical Center Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiss
authors.affiliation: Institute of Human Genetics, University Medical Center Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany. lsmorag@gwdg.de.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Smorag
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019755:Carbon-Carbon Lyases; D003067:Coenzymes / Q000096:biosynthesis / Q000235:genetics*; D003545:Cysteine / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D019271:Hypoxanthine / Q000097:blood / Q000652:urine; D008664:Metal Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D008667:Metalloproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000090006:Molybdenum Cofactors; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D011621:Pteridines; D019820:Xanthine / Q000097:blood / Q000652:urine
chemical_list: D019755:Carbon-Carbon Lyases; D003067:Coenzymes; D003545:Cysteine; D019271:Hypoxanthine; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D009687:Nuclear Proteins; D011621:Pteridines; D019820:Xanthine; C011119:S-sulphocysteine; C022261:molybdopterin; C114840:MOCS1 protein, human