Mutations in the hepatocyte nuclear factor-1 alpha gene in Caucasian families originally classified as having Type I diabetes

Mutations in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene are t he cause of maturity-onset diabetes of the young type 3 (MODY3), which is c haracterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) dia betes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large p opulation-based sample of unrelated Danish Caucasian Type I diabetic patien ts with an affected first degree relative, 39 patients (6.7%) who did not c arry any high-risk HLA-haplotypes, i.e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing o f the coding region and the minimal promoter of the HNF-1 alpha gene. Four of the 39 Type I diabetic patients (10%) were identified as carrying mutati ons in the HNF-1 alpha gene. One patient carried a missense mutation (Glu48 Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exo n 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with di abetes, and were not identified in 84 unrelated, healthy subjects. Furtherm ore, family history in three of the four families showed diabetes in four c onsecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10% of Danish. diabetic patients without a high-risk HLA -haplotype, originally classified as having Type I diabetes could have diab etes caused by mutations in the HNF-1 alpha gene. Clinical awareness of fam ily history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients.