Genetic Disorders – Development
Kidney International (2003) 63, 1645–1651; doi:10.1046/j.1523-1755.2003.00903.x
Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1
gene mutation
Coralie Bingham, Sian Ellard, William G van't Hoff, H Anne Simmonds, Anthony M Marinaki, Michael K Badman, Peter H Winocour, Amanda Stride, Christopher R Lockwood, Anthony J Nicholls, Katharine R Owen, Ghislaine Spyer, Ewan R Pearson and Andrew T Hattersley
Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, United Kingdom; Nephro-Urology Unit, Institute of Child Health, University College London, London, United Kingdom; Purine Research Unit, GKT Guy's Hospital, London, United Kingdom; and East and North Hertfordshire NHS Trust, Welwyn Garden City, United Kingdom
Correspondence: Dr. Coralie Bingham, Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Road, Exeter, Devon, UK EX2 5AX. E-mail C.Bingham@exeter.ac.uk
Received 30 May 2002; Revised 25 September 2002; Re-revised 20 November 2002; Accepted 13 December 2002.
Abstract
Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1
gene mutation.
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)-1
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-1
gene in some FJHN kindreds we sequenced the HNF-1 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-1 mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1 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-1 subjects compared with the normal control subjects (384 
mol/L vs. 264 mol/L, P = 0.002) and the type 2 diabetic subjects (397 mol/L vs. 271 mol/L, P = 0.01). Comparison of serum urate levels in the HNF-1 subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 mol/L vs. 352 mol/L, P = 0.2).
Conclusion
Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1 mutations, but the mechanism is uncertain. Families with HNF-1 mutations may fit diagnostic criteria for FJHN. Identification of HNF-1 patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.
Keywords:
transcription factors, HNF-1 mutation, hyperuricemia, familial renal disease, juvenile gout
