title: Homozygosity for uromodulin disorders: FJHN and MCKD-type 2.
abstract: BACKGROUND
  Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN) are heritable renal diseases with autosomal-dominant transmission and shared features, including polyuria, progressive renal failure, and abnormal urate handling, which leads to hyperuricemia and gout. Mutations of the UMOD gene, disrupting the tertiary structure of uromodulin, cause MCKD2 and FJHN.
  
  
  METHODS
  Haplotype analysis of a large Spanish family with MCKD was carried out to determinate genetic linkage to MCKD2 locus. Mutation detection was performed by direct sequencing of the UMOD gene. The level of Tamm-Horsfall protein in the urine was measured by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis.
  
  
  RESULTS
  Linkage to MCKD2 locus was demonstrated (LOD score: 4.13), and a known pathogenic uromodulin mutation was found in exon 4, corresponding to Cys255Tyr, disrupting the light chain binding domain of the protein. In this consanguineous family there were three patients homozygous for the C255Y mutation, and multiple heterozygous cases, allowing the MCKD phenotypes associated with one or two mutant alleles to be compared. The homozygous individuals survived to adulthood, although presenting an earlier onset of hyperuricemia and faster progression to end-stage renal disease than heterozygous individuals. Western analysis revealed lower levels of urine THP in one heterozygous patient compared with a normal control patient, both with normal renal function.
  
  
  CONCLUSIONS
  The study shows that individuals with two UMOD mutations are viable, but they do have more severe disease on average than heterozygotes. This family sheds light on the possible disease mechanism in this disorder.
authors.affiliation: Laboratorio de Investigación en Nefroloxía, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Wânia
authors.initials: W
authors.lastname: Rezende-Lima
authors.forename: Kleber S
authors.initials: KS
authors.lastname: Parreira
authors.forename: Miguel
authors.initials: M
authors.lastname: García-González
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira
authors.forename: Julio F
authors.initials: JF
authors.lastname: Banet
authors.forename: Xosé M
authors.initials: XM
authors.lastname: Lens
mesh_terms: D000328:Adult; D005260:Female; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000235:genetics* / Q000652:urine; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D012720:Severity of Illness Index; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin