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Nephrol Dial Transplant. 2017 Dec 1;32(12):1994-1999. doi: 10.1093/ndt/gfx066.

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

Author information

1
Institute for Cell and Molecular Biosciences, Newcastle University Medical School, Newcastle upon Tyne, UK.
2
Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
3
Renal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
4
Academic Department of Medical Genetics, Cambridge Biomedical Campus, Cambridge, UK.
5
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.

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.

KEYWORDS:

Tamm-Horsfall protein; gout; homozygous mutation; tubulointerstitial kidney disease; uromodulin

PMID:
28605509
PMCID:
PMC5837645
DOI:
10.1093/ndt/gfx066
[Indexed for MEDLINE]
Free PMC Article

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