4.0 Article

Deletion of Mocos Induces Xanthinuria with Obstructive Nephropathy and Major Metabolic Disorders in Mice

Journal

KIDNEY360
Volume 2, Issue 11, Pages 1793-1806

Publisher

AMER SOC NEPHROLOGY
DOI: 10.34067/KID.0001732021

Keywords

nephrolithiasis; cyrstallopathy; inflammation; kidney diseases; kidney stones; MOCOS; obstructive nephropathy; oxidative stress; purine-pyrimidine metabolism; inborn errors; purines; renal failure; transgenic mouse; uremia; urethral diseases; urogenital abnormalities; xanthinuria

Funding

  1. Centre National de la Recherche Scientifique (CNRS)
  2. Institut National de la Sante et de la Recherche Medicale (INSERM), University of Orleans
  3. University of Tours
  4. European funding in Region Centre-Val de Loire(FEDER) [2016-001103665BIO-TARGET 2015-2018, EX0057565BIO-TARGETII]

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Xanthinuria type II is a rare autosomal purine disorder that can lead to lethal obstructive nephropathy, highlighting the importance of early diagnosis and treatment.
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.

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