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Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients

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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.

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Fig. 1

The scheme was modified from Reiss and Hahnewald (2011)

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Acknowledgments

We thank our animal caretakers Stephan Wolf, Jennifer Fleming, Lea Piontek and Christina Ahlbrecht for invaluable help with animal care. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (RE 768/16-1).

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Authors and Affiliations

  1. Institute of Human Genetics, University Medical Center Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany

    Joanna Jakubiczka-Smorag, Peter Burfeind, Jochen Reiss & Lukasz Smorag

  2. Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zuelpicher Strasse 47, 50674, Koeln, Germany

    Jose Angel Santamaria-Araujo, Avadh Kumar & Guenter Schwarz

  3. Institute of Neuropathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075, Goettingen, Germany

    Imke Metz & Wolfgang Brueck

  4. Institute of Pathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075, Goettingen, Germany

    Samy Hakroush

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  1. Joanna Jakubiczka-Smorag
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  2. Jose Angel Santamaria-Araujo
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  3. Imke Metz
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  4. Avadh Kumar
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  7. Guenter Schwarz
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  9. Jochen Reiss
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  10. Lukasz Smorag
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Correspondence to Lukasz Smorag.

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The authors declare no conflicts of interest. This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Nds. Landesamt für Verbraucherschutz und Lebensmittelsicherheit (LAVES), Dezernat 33, Röverskamp 5, 26203 Wardenburg).

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Jakubiczka-Smorag, J., Santamaria-Araujo, J.A., Metz, I. et al. Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients. Hum Genet 135, 813–826 (2016). https://doi.org/10.1007/s00439-016-1676-4

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