J Med Genet 43:84-90 doi:10.1136/jmg.2005.032854
  • Letters to JMG

Mutations in hepatocyte nuclear factor-1β and their related phenotypes

  1. E L Edghill,
  2. C Bingham,
  3. S Ellard,
  4. A T Hattersley
  1. Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
  1. Correspondence to:
 Professor Andrew T Hattersley
 Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Road, Exeter, EX2 5AX, UK; A.T.Hattersley{at}
  • Accepted 24 May 2005
  • Revised 23 May 2005
  • Published Online First 1 June 2005


Background: Hepatocyte nuclear factor-1 beta (HNF-1β) is a widely distributed transcription factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF-1β mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities.

Methods: We sequenced the HNF-1β gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/family history of diabetes.

Results: Twenty three different heterozygous HNF-1β mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients (four with glomerulocystic kidney disease, GCKD) and diabetes in 11/23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity-onset diabetes of the young (MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships.

Conclusion: We report the largest series to date of HNF-1β mutations and confirm HNF-1β mutations as an important cause of renal disease. Despite the original description of HNF-1β as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF-1β mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities.


  • Published Online First 8 June 2005

  • We thank the National Kidney Research Fund (grant TF13/2000), Exeter Kidney Unit Development Fund, Royal Devon and Exeter NHS Foundation Trust R&D Directorate, British Medical Association, and Wellcome Trust who all supported this work. ATH is a Wellcome Trust research leave fellow and CB Bingham was an NKRF clinical research fellow

  • Competing interests: none declared

  • Ethics approval was given for this study by the South West Multi-Centre Research Ethics Committee