Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1β gene mutation

TY - JOUR

T1 - Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1β gene mutation

AU - Bingham, Coralie

AU - Ellard, Sian

AU - Van't Hoff, William G.

AU - Simmonds, H. Anne

AU - Marinaki, Anthony M.

AU - Badman, Michael K.

AU - Winocour, Peter H.

AU - Stride, Amanda

AU - Lockwood, Christopher R.

AU - Nicholls, Anthony J.

AU - Owen, Katharine R.

AU - Spyer, Ghislaine

AU - Pearson, Ewan R.

AU - Hattersley, Andrew T.

PY - 2003/5

Y1 - 2003/5

N2 - 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)-1β 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-1β gene in some FJHN kindreds we sequenced the HNF-1β 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-1β mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1β mutations.Results: A splice-site mutation in intron 2, designated IVS2+IG>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1β subjects compared with the normal control subjects (384 μmol/L vs. 264 μmol/L, P = 0.002) and the type 2 diabetic subjects (397 μmol/L vs. 271 p, mol/L, P = 0.01). Comparison of serum urate levels in the HNF-1β subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 μmol/L vs. 352 μmol/L, P = 0.2).Conclusion: Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1β mutations, but the mechanism is uncertain. Families with HNF-1β mutations may fit diagnostic criteria for FJHN. Identification of HNF-1β patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

AB - 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)-1β 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-1β gene in some FJHN kindreds we sequenced the HNF-1β 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-1β mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1β mutations.Results: A splice-site mutation in intron 2, designated IVS2+IG>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1β subjects compared with the normal control subjects (384 μmol/L vs. 264 μmol/L, P = 0.002) and the type 2 diabetic subjects (397 μmol/L vs. 271 p, mol/L, P = 0.01). Comparison of serum urate levels in the HNF-1β subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 μmol/L vs. 352 μmol/L, P = 0.2).Conclusion: Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1β mutations, but the mechanism is uncertain. Families with HNF-1β mutations may fit diagnostic criteria for FJHN. Identification of HNF-1β patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

KW - Familial renal disease

KW - HNF-1β mutation

KW - Hyperuricemia

KW - Juvenile gout

KW - Transcription factors

UR - https://www.scopus.com/pages/publications/0037408284

U2 - 10.1046/j.1523-1755.2003.00903.x

DO - 10.1046/j.1523-1755.2003.00903.x

M3 - Article

C2 - 12675839

AN - SCOPUS:0037408284

SN - 0085-2538

VL - 63

SP - 1645

EP - 1651

JO - Kidney International

JF - Kidney International

IS - 5

ER -