title: Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.
abstract: BACKGROUND
  Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds.
  
  
  METHODS
  To assess a possible role for the HNF-1beta gene in some FJHN kindreds we sequenced the HNF-1beta gene in subjects from three unrelated FJHN families with atypical features of renal cysts or abnormalities of renal development. We also compared serum urate levels in subjects with HNF-1beta mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1beta mutations.
  
  
  RESULTS
  A splice-site mutation in intron 2, designated IVS2+1G>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1beta subjects compared with the normal control subjects (384 micromol/L vs. 264 micromol/L, P = 0.002) and the type 2 diabetic subjects (397 micromol/L vs. 271 micromol/L, P = 0.01). Comparison of serum urate levels in the HNF-1beta subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 micromol/L vs. 352 micromol/L, P = 0.2).
  
  
  CONCLUSIONS
  Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.
authors.affiliation: Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, United Kingdom. C.Bingham@exeter.ac.uk
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: William G
authors.initials: WG
authors.lastname: van't Hoff
authors.forename: H Anne
authors.initials: HA
authors.lastname: Simmonds
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.forename: Michael K
authors.initials: MK
authors.lastname: Badman
authors.forename: Peter H
authors.initials: PH
authors.lastname: Winocour
authors.forename: Amanda
authors.initials: A
authors.lastname: Stride
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lockwood
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Nicholls
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Spyer
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D006073:Gout / Q000235:genetics*; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta