Universität zu Köln

Jakubiczka-Smorag, Joanna, Santamaria-Araujo, Jose Angel, Metz, Imke, Kumar, Avadh, Hakroush, Samy, Brueck, Wolfgang, Schwarz, Guenter ORCID: 0000-0002-2118-9338, Burfeind, Peter, Reiss, Jochen and Smorag, Lukasz (2016). Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients. Hum. Genet., 135 (7). S. 813 - 827. NEW YORK: SPRINGER. ISSN 1432-1203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jakubiczka-Smorag, Joanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Santamaria-Araujo, Jose Angel UNSPECIFIED UNSPECIFIED UNSPECIFIED Metz, Imke UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumar, Avadh UNSPECIFIED UNSPECIFIED UNSPECIFIED Hakroush, Samy UNSPECIFIED UNSPECIFIED UNSPECIFIED Brueck, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED Burfeind, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiss, Jochen UNSPECIFIED UNSPECIFIED UNSPECIFIED Smorag, Lukasz UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271807
DOI:	10.1007/s00439-016-1676-4
Journal or Publication Title:	Hum. Genet.
Volume:	135
Number:	7
Page Range:	S. 813 - 827
Date:	2016
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language XANTHINE OXIDOREDUCTASE; HEREDITARY XANTHINURIA; SULFITE OXIDASE; NEURON LOSS; EXPRESSION; MUTATIONS; BRAIN; GENE; DEHYDROGENASE; INHIBITION Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27180