[A Dutch family with an autosomal dominant form of diabetes mellitus as a result of a mutation in the HNF1 alpha-gene (MODY3)].

OBJECTIVE

To study the molecular genetic basis of an autosomal dominant form of diabetes mellitus in a Dutch family.

DESIGN

Descriptive.

SETTING

Academic Hospital Nijmegen, the Netherlands and Laboratories for Molecular Genetics, Birmingham and Exeter, Great Britain.

METHODS

A large pedigree with maturity-onset diabetes of the young (MODY) was studied by taking a history and by performing laboratory analysis; DNA was isolated from peripheral blood lymphocytes and linkage analysis was carried out using genetic markers near known MODY loci. As linkage to the MODY3 gene (encoding for the transcription factor hepatocyte nuclear factor (HNF)1 alpha) was suggested, all exons of the gene were sequenced for mutation detection.

RESULTS

Of the 27 family members 13 were affected by diabetes. Diabetes was diagnosed at a mean age of 36.7 years, with four family members diagnosed before the age of 25. Nearly all patients were treated with diet/oral antidiabetics. Diabetic family members had lower fasting (specific) insulin concentrations than normoglycaemic family members (53.8 (SD: 5.4) versus 90.4 (SD: 12.9) pmol/l; p < 0.05). Linkage to the MODY3 gene was established. Further investigation showed a mutation in exon 2 of the gene.

CONCLUSION

This Dutch family suffered from an autosomal form of diabetes mellitus caused by a mutation in the HNFI alpha gene (MODY3). Phenotypically, the diabetes appeared to be relatively mild; it was characterised by impaired insulin secretion.