title: Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy.
abstract: 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.affiliation: Department of Medical Genetics, Medical Faculty of the Charité, Berlin, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Nico
authors.initials: N
authors.lastname: Ruf
authors.forename: Ilenia
authors.initials: I
authors.lastname: Bernascone
authors.forename: Kai
authors.initials: K
authors.lastname: Sacherer
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lamorte
authors.forename: Hans-Hellmut
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D005819:Genetic Markers; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007668:Kidney; D007674:Kidney Diseases / Q000235:genetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058949:Uromodulin
chemical_list: D017931:DNA Primers; D005819:Genetic Markers; D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin