title: Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.
abstract: BACKGROUND
  Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic.
  
  
  OBJECTIVE
  To identify the gene and associated mutation(s) responsible for FJHN and MCKD2.
  
  
  METHODS
  Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family).
  
  
  RESULTS
  We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2.
  
  
  CONCLUSIONS
  These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
authors.affiliation: University of Pittsburgh, School of Dental Medicine, Division of Oral Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. hart@sdmgenetics.pitt.edu
authors.forename: T C
authors.initials: TC
authors.lastname: Hart
authors.forename: M C
authors.initials: MC
authors.lastname: Gorry
authors.forename: P S
authors.initials: PS
authors.lastname: Hart
authors.forename: A S
authors.initials: AS
authors.lastname: Woodard
authors.forename: Z
authors.initials: Z
authors.lastname: Shihabi
authors.forename: J
authors.initials: J
authors.lastname: Sandhu
authors.forename: B
authors.initials: B
authors.lastname: Shirts
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.forename: M M
authors.initials: MM
authors.lastname: Barmada
authors.forename: A J
authors.initials: AJ
authors.lastname: Bleyer
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002675:Child, Preschool; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006073:Gout / Q000235:genetics / Q000503:physiopathology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics* / Q000503:physiopathology; D008126:Lod Score; D008297:Male; D009088:Mucoproteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000503:physiopathology; D051437:Renal Insufficiency / Q000235:genetics* / Q000503:physiopathology; D058949:Uromodulin
chemical_list: D005819:Genetic Markers; D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin