Nephrol Dial Transplant Vol. 19 No. 12 © ERA-EDTA 2004; all rights reserved
Brief Report
Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy
1 Department of Medical Genetics, Medical Faculty of the Charité, 2 Max Delbrück Center for Molecular Medicine, 3 Nephrology Section, Charité Campus Mitte, 4 Nephrology Section, Franz Volhard Clinic, HELIOS Klinikum, Charité Campus Buch, Berlin, 5 Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Technical University, Dresden, Germany, 6 DIBIT San Rafaele Scientific Institute, Milan, 7 Dulbecco Telethon Institute, Rome, Italy
Correspondence and offprint requests to: Friedrich C. Luft, Wiltberg Strasse 50, 13125 Berlin, Germany. Email: luft{at}fvk-berlin.de
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.
Keywords: familial juvenile hyperuricaemic nephropathy, genetics; interstitial nephritis, uric acid, uromodulin, Tamm–Horsfall glycoprotein
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