Lysine 117 residue is essential for the function of the hepatocyte nuclear factor 1α

Hepatocyte nuclear factor 1α (HNF1α) plays essential roles in controlling development and metabolism, its mutations are clearly linked to the occurrence of maturity-onset diabetes of the young (MODY3) in humans. Lysine 117 (K117) to glutamic acid (E117) mutation in the HNF1α gene has been clinically associated with MODY3, but no functional data on this variant is available. Here, we addressed the role of lysine 117 in HNF1α function using a knock-in animal model and site-directed mutagenesis. HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome and progressive wasting syndrome. These phenotypes were very similar to those of mice with complete HNF1α deficiency, suggesting that K117 is critical to HNF1α functions. K117E homozygotes developed diabetes in the early postnatal period. The relative deficiency of serum insulin levels and the normal response to insulin treatment in homozygous mice were markedly similar to those in the MODY3 disorder in humans. Moreover, K117E heterozygous mutant causes age-dependent glucose intolerance which is similar with the pathogenesis of MODY3 as well. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization. Collectively. our findings reveal a previously unappreciated role of POU domain of HNF1α in homodimerization, and also provide important clues for identifying the molecular basis of HNF1α related diseases such as MODY3.