title: Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations.
abstract: BACKGROUND
  Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations.
  
  
  OBJECTIVE
  To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations.
  
  
  METHODS
  Multicenter, descriptive study.
  
  
  METHODS
  2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology.
  
  
  METHODS
  8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring.
  
  
  METHODS
  Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results.
  
  
  RESULTS
  All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients.
  
  
  CONCLUSIONS
  Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations.
  
  
  CONCLUSIONS
  Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.
authors.affiliation: Fédération des Services de Biochimie, Laboratoire de Biologie Moléculaire, Hôpital Saint-Antoine, Paris, France. christine.bellanne@sat.ap-hop-paris.fr
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Danièle
authors.initials: D
authors.lastname: Dubois-Laforgue
authors.forename: Séverine
authors.initials: S
authors.lastname: Clauin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Beaufils
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Wilhelm
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
authors.forename: Laure-Hélène
authors.initials: LH
authors.lastname: Noël
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
authors.forename: José
authors.initials: J
authors.lastname: Timsit
mesh_terms: D000328:Adult; D001284:Atrophy; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology; D010188:Exocrine Pancreatic Insufficiency / Q000150:complications / Q000473:pathology; D005799:Genes, Dominant; D005835:Genitalia / Q000002:abnormalities; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta