Delphine Sedda1, Claire Mackowiak1, Julie Pailloux1, Elodie Culerier1, Ana Dudas1, Pauline Rontani2, Nicolas Erard2, Antoine Lefevre3, Sylvie Mavel3, Patrick Emond3,4,5, Frederic Foucher6, Marc Le Bert1, Valerie F J Quesniaux1, Michael J Mihatsch7, Bernhard Ryffel1, Madeleine Erard-Garcia1. 1. Experimental and Molecular Immunology and Neurogenetics (INEM), Orléans University, Centre National de la Recherche Scientifique (CNRS) UMR7355, Orléans, France. 2. Institute of NeuroPhysiopathology (INP), Aix-Marseille University, CNRS UMR7051, Marseille, France. 3. iBrain, Tours University, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1253, Tours, France. 4. Division of In Vitro Nuclear Medicine, Regional University Hospital of Tours, Tours, France. 5. PST Analysis of Biological Systems, Tours University, Tours, France. 6. Center for Molecular Biophysics (CBM), CNRS UPR4301, Orléans, France. 7. Institute for Pathology, University Hospital of Basel, Basel, Switzerland.
Abstract
Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Results: Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Conclusions: Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Results: Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Conclusions: Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Authors: Saeed R Khan; Margaret S Pearle; William G Robertson; Giovanni Gambaro; Benjamin K Canales; Steeve Doizi; Olivier Traxer; Hans-Göran Tiselius Journal: Nat Rev Dis Primers Date: 2016-02-25 Impact factor: 52.329