MATURITY-ONSET DIABETES OF THE YOUNG DUE TO A MUTATION IN THE HEPATOCYTE NUCLEAR FACTOR-4-ALPHA BINDING-SITE IN THE PROMOTER OF THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE

Recent studies have shown that mutations in the transcription factor h epatocyte nuclear factor (HNF)-1 alpha are the cause of one form of ma turity-onset diabetes of the young (MODY3). These studies have identif ied mutations in the mRNA, and protein coding regions of this,bene tha t result in the synthesis of an abnormal mRNA or protein. Here, we rep ort an Italian family in which an A-->C substitution at nucleotide -58 of tile promoter region of the HNF-1 alpha gene cosegregates with MOD Y. This mutation is located in a highly conserved region of the promot er and disrupts the binding site for the transcription factor HNF-4 al pha, mutations in the gene encoding HNF-4 alpha being another cause of MODY (MODY1). This result demonstrates that decreased levels of HDF-1 alpha per se can cause MODY. Moreover, it indicates that both the pro moter and coding regions of the HNF-1 alpha gene should be screened fo r mutations in subjects thought to have MODY because of mutations in t his gene.