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A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion


Edwards, Noel; Olinger, Eric; Adam, Jennifer; Kelly, Michael; Schiano, Guglielmo; Ramsbottom, Simon A; Sandford, Richard; Devuyst, Olivier; Sayer, John A (2017). A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion. Nephrology, Dialysis, Transplantation, 32(12):1994-1999.

Abstract

Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.

Abstract

Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2017
Deposited On:20 Feb 2018 15:23
Last Modified:19 Aug 2018 14:24
Publisher:Oxford University Press
ISSN:0931-0509
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ndt/gfx066
PubMed ID:28605509
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_169850
  • : Project TitlePhysiopathology of endolysosomal diseases in the kidney: Lysosomal function, autophagy, and epithelial differentiation.

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