The type 3 form of maturity-onset diabetes of the young (M0DY3) results from mutations in the gene encoding the transcription factor, hepatocyte nuclear factor-1α (HNF-1α). The mechanism by which mutations in only one allele of the HNF-1α gene impair pancreatic β-cell function is unclear. The functional form of HNF-1α is a dimer—either a homodimer or a heterodimer with the structurally related protein HNF-1β—that binds to and activates transcription of the genes whose expression it regulates. HNF-1α is composed of three functional domains: an amino-terminal dimerization domain (amino acids 1–32), a DNA-binding domain with POU-like and homeodomain-like motifs (amino acids 150–280), and a COOH-terminal transactivation domain (amino acids 281–631). Because the dimerization domain is intact in many of the mutant forms of HNF-1α found in MODY subjects, these mutant proteins may impair pancreatic β-cell function by forming nonproductive dimers with wild-type protein, thereby inhibiting its activity; that is, they are dominant-negative mutations. This hypothesis was tested by comparing the functional properties of the frameshift mutation P291fsinsC, the most common mutation identified to date in MODY3 patients, and wild-type HNF-1α. P291fsinsC-HNF-1α showed no transcriptional transactivation activity in HeLa cells, which lack endogenous HNF-1α. Overexpression of P291fsinsC-HNF-1α in MIN6 cells, a mouse β-cell line, resulted in an ∼40% inhibition of the endogenous HNF1α activity in a dosage-dependent manner. Furthermore, heterodimer formation between wild-type and P291fsinsC mutant proteins were observed by electrophoretic mobility shift assay. These data suggest that the P291fsinsC mutation in HNF-1α functions as a dominant-negative mutation. However, other mutations, such as those in the promoter region and dimerization domain, may represent loss of function mutations. Thus mutations in the HNF-1α gene may lead to β-cell dysfunction by two different mechanisms.

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