Affiliation:
1. Department of Diabetes and Metabolism, Division of Medicine, University of Bristol, Bristol, U.K.
2. Centre for Molecular Genetics, Peninsular Medical School, Exeter, U.K.
3. Chiltern Diabetes Centre, Wycombe Hospital, High Wycombe, Buckinghamshire, U.K.
Abstract
OBJECTIVE—HNF-1α 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-1α 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-1α 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-1α 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-1α mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1α gene to those with a family history of diabetes who also test negative for islet autoantibodies.
Publisher
American Diabetes Association
Subject
Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
284 articles.
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