Hepatocyte nuclear factor-1α gene mutations and diabetes in Norway

Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene cause maturity-onset diabetes of the young (MODY), type 3. To estimate the prevalence of MODY3 in Norwegian diabetic pedigrees, we screened a total of 130 families for lHNF-1alpha mutations; 42 families with clinical MODY, 75 with suspected MODY, and 13 pedigrees with multiplex type 1 diabetes. Twenty-two families with clinical MODY,15 families with suspected MODY, and one family with type 1 diabetes multiplex harbored HNF-1alpha mutations. Thus, in about half of Norwegian families with clinical MODY, mutations in the HNF-1alpha gene could be detected. Eight of the 18 different mutations identified were novel (G47E, T196fsdelCCAA, IVS3-1G>A, S256T, A276D, S445fsdelAG, M522V, and S531T). Haplotypes were determined for recurrent mutations, indicating a founder effect in Norway for the hot-spot mutation P291fsinsC and possibly also for P112L and R131W. To examine the molecular mechanisms underlying MODY3, we investigated the functional properties of 13 HNF-1alpha mutations. Two mutant HNF-1alpha proteins (R171X, R263C) were unable to bind DNA and at least five mutants (R131W, R171X, P379fsdelCT, S445fsdelAG, and Q466X) showed defective nuclear translocation. Transcriptional activation was reduced for most of the MODY3-associated mutants. Accordingly, the functional studies of HNF-1alpha mutants indicate that beta-cell dysfunction in MODY3 is caused by loss-of-function mechanisms like reduced DNA binding, impaired transcriptional activation, and defects in subcellular localization.