Journal Article

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

Sigrid Tinschert, Nico Ruf, Ilenia Bernascone, Kai Sacherer, Giuseppe Lamorte, Hans-Hellmut Neumayer, Peter Nürnberg, Friedrich C. Luft and Luca Rampoldi

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 19, issue 12, pages 3150-3154
Published in print December 2004 | ISSN: 0931-0509
Published online December 2004 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfh524
Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy

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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

Journal Article.  3147 words.  Illustrated.

Subjects: Nephrology

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