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.
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.
Authors: Sian E Piret; Patrick Danoy; Karin Dahan; Anita A C Reed; Karena Pryce; William Wong; Rosa J Torres; Juan G Puig; Thomas Müller; Peter Kotanko; Karl Lhotta; Olivier Devuyst; Matthew A Brown; Rajesh V Thakker Journal: Hum Genet Date: 2010-10-26 Impact factor: 4.132
Authors: Jonathan L Moskowitz; Sian E Piret; Karl Lhotta; Thomas M Kitzler; Adam P Tashman; Erin Velez; Rajesh V Thakker; Peter Kotanko Journal: Clin J Am Soc Nephrol Date: 2013-05-30 Impact factor: 8.237
Authors: Siân E Williams; Anita A C Reed; Juris Galvanovskis; Corinne Antignac; Tim Goodship; Fiona E Karet; Peter Kotanko; Karl Lhotta; Vincent Morinière; Paul Williams; William Wong; Patrik Rorsman; Rajesh V Thakker Journal: Hum Mol Genet Date: 2009-05-22 Impact factor: 6.150