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.

RESEARCH DESIGN AND 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: A Paul Lambert, Sian Ellard, Lisa I S Allen, Ian W Gallen, Kathleen M Gillespie, Polly J Bingley, Andrew T Hattersley
• Journal: Diabetes care (Diabetes Care) Vol. 26 Issue 2 Pg. 333-7 (Feb 2003) ISSN: 0149-5992 [Print] United States
• PMID: 12547858 (Publication Type: Journal Article)

Chemical References

• Autoantibodies
• Codon, Nonsense
• DNA-Binding Proteins
• HNF1A protein, human
• HNF1B protein, human
• Hepatocyte Nuclear Factor 1-alpha
• Histocompatibility Antigens Class II
• Nuclear Proteins
• Transcription Factors
• islet cell antibody
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-beta

Topics

• Adolescent
• Adult
• Amino Acid Substitution
• Autoantibodies (analysis)
• Base Sequence (genetics)
• Child
• Codon, Nonsense
• DNA-Binding Proteins
• Diabetes Mellitus, Type 1 (genetics, immunology)
• Female
• Genotype
• Haplotypes
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-alpha
• Hepatocyte Nuclear Factor 1-beta
• Heterozygote
• Histocompatibility Antigens Class II (genetics)
• Homozygote
• Humans
• Male
• Mutation (genetics)
• Nuclear Proteins
• Pedigree
• Phenotype
• Prospective Studies
• Transcription Factors (genetics)