Functional Study of the E276Q Mutant Hepatocyte Nuclear Factor-4 alpha Found in Type 1 Maturity-Onset Diabetes of the Young: Impaired Synergy With Chicken Ovalbumin Upstream Promoter Transcription Factor II on the Hepatocyte Nuclear Factor-1 Promoter

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Seven mutations in the hepatocyte nuclear factor (HNF)-4 alpha gene have been shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a monogenic form of type 2 diabetes. Up to now, only the functional properties of two MODY 1 HNF-4 alpha mutants, Q268X and V393I, have been investigated to address how the mutations in the HNF-4 alpha gene, found by genetic studies, can give rise to impaired activities of mutated HNF-4 alpha proteins and can cause this disease. The E276Q mutation results in a nonconservative substitution occurring in the HNF-4 alpha E domain, which is involved in dimerization and transactivation activities as well as in protein-protein interactions with other transcription factors or coactivators. Using the mutated human HNF-4 alpha 2, we have found that, in the absence of chicken ovalbumin upstream promoter transcription factor II (COUP TFII), the E276Q substitution does not significantly affect the dimerization and transactivating activities of HNF-4 alpha, at least on the promoters studied herein. On the other hand, in the presence of COUP TFII, the substitution impairs the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an alteration of their interaction. HNF-1 expression plays a crucial role in transactivation of insulin promoter and of numerous genes coding for enzymes involved in glucose homeostasis. Therefore, its downregulation resulting from the E276Q mutation in HNF-4 alpha gene most probably impairs the function of pancreatic beta-cells. Diabetes 48:1162-1167, 1999

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