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.