title: Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes.
abstract: OBJECTIVE
  HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely.
  
  
  METHODS
  In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed.
  
  
  RESULTS
  At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment.
  
  
  CONCLUSIONS
  Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.
authors.affiliation: Department of Diabetes and Metabolism, Division of Medicine, University of Bristol, UK. a.p.Lambert@bristol.ac.uk
authors.forename: A Paul
authors.initials: AP
authors.lastname: Lambert
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Lisa I S
authors.initials: LI
authors.lastname: Allen
authors.forename: Ian W
authors.initials: IW
authors.lastname: Gallen
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001323:Autoantibodies / Q000032:analysis; D001483:Base Sequence / Q000235:genetics; D002648:Child; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005838:Genotype; D006239:Haplotypes; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006579:Heterozygote; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D000949:Histocompatibility Antigens Class II; D009687:Nuclear Proteins; D014157:Transcription Factors; C024211:islet cell antibody; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta