Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy

Nephrol Dial Transplant. 2004 Dec;19(12):3150-4. doi: 10.1093/ndt/gfh524.


Background: Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal-dominant disorder featuring hyperuricaemia, low fractional urate excretion, interstitial nephritis and chronic renal failure. The responsible gene UMOD was recently identified. UMOD encodes for uromodulin or Tamm-Horsfall glycoprotein, the most abundant protein in normal urine. We encountered a family with FJHN and identified a novel UMOD mutation in exon 6.

Methods: We sequenced the gene in all family members, identified the mutation, and verified its presence in the affected members. We next performed functional studies of the mutant protein by immunofluorescence and FACS analysis on transfected cells.

Results: The mutation p.C347G (c.1039T > G) results in a conserved cysteine to glycine amino acid substitution in the uromodulin zona pellucida (ZP) domain. The cell studies showed that the novel uromodulin mutation causes a delay in protein export to the plasma membrane due to its retention in the endoplasmic reticulum.

Conclusions: We describe the first reported mutation mapping in the ZP uromodulin domain. Our data provide further evidence showing why the excretion of uromodulin is reduced in this syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • DNA Primers
  • Female
  • Flow Cytometry
  • Genetic Markers
  • Humans
  • Hyperuricemia / genetics*
  • Kidney
  • Kidney Diseases / genetics*
  • Kidney Diseases / urine
  • Male
  • Middle Aged
  • Mucoproteins / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • Uromodulin


  • DNA Primers
  • Genetic Markers
  • Mucoproteins
  • UMOD protein, human
  • Uromodulin