title: Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene.
abstract: BACKGROUND
  Uromodulin (Tamm Horsfall glycoprotein) is the most abundant protein found in normal human urine. Its function has yet to be determined. Identifying mutations in the uromodulin gene may be helpful in understanding the function of uromodulin. There has been 1 report of 4 families suffering from mutations in the uromodulin gene, resulting in the autosomal dominant transmission of hypouricosuric hyperuricemia and chronic renal failure. This case report describes another family with similar clinical manifestations.
  
  
  METHODS
  A family was identified with clinical characteristics of hypouricosuric hyperuricemia and renal failure occurring in a mother and daughter. Clinical characteristics were identified, and laboratory studies were obtained in the proband and the proband's daughter. A genetic analysis was performed to evaluate for mutations in the uromodulin gene.
  
  
  RESULTS
  The proband suffered from hyperuricemia at an early age and progressive renal failure with end-stage renal disease developing at age 49 years. The proband's daughter suffered from hyperuricemia, a reduced fractional excretion of uric acid, and mild renal insufficiency. A g.2105G > A mutation in exon 4 of the uromodulin gene resulting in a substitution of tyrosine for cysteine was identified in both the proband and the proband's daughter. The clinical characteristics were similar to those of other patients suffering from uromodulin mutations and to those of patients suffering from medullary cystic kidney disease type 2 and familial juvenile hyperuricemic nephropathy.
  
  
  CONCLUSIONS
  Uromodulin associated kidney disease results in hyperuricemia and renal failure. The specific uromodulin mutation found in this family is consistent with the hypothesis that mutations disrupt highly conserved cysteine residues in the uromodulin protein. Potential mechanisms for these pathologic changes are discussed. The authors would appreciate referral of other families for screening for mutations.
authors.affiliation: Section on Nephrology,Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. ableyer@wfubmc.edu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bleyer
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Sandhu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gorry
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Hart
mesh_terms: D019943:Amino Acid Substitution; D002648:Child; D003545:Cysteine / Q000737:chemistry; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006073:Gout / Q000209:etiology; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin; D003545:Cysteine