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

Seven mutations in the hepatocyte nuclear factor (HNF)-4 alpha gene have be en shown to correlate with type 1 maturity-onset diabetes of the young (MOD Y 1), a monogenic form of type 2 diabetes. Up to now, only the functional p roperties of two MODY 1 HNF-4 alpha mutants, Q268X and V393I, have been inv estigated to address how the mutations in the HNF-4 alpha gene, found by ge netic studies, can give rise to impaired activities of mutated HNF-4 alpha proteins and can cause this disease. The E276Q mutation results in a noncon servative substitution occurring in the HNF-4 alpha E domain, which is invo lved in dimerization and transactivation activities as well as in protein-p rotein interactions with other transcription factors or coactivators. Using the mutated human HNF-4 alpha 2, we have found that, in the absence of chi cken ovalbumin upstream promoter transcription factor II(COUP TFII), the E2 76Q substitution does not significantly affect the dimerization and transac tivating activities of HNF-4 alpha, at least on the promoters studied herei n. On the other hand, in the presence of COUP TFII, the substitution impair s the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impai red 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 i n transactivation of insulin promoter and of numerous genes coding for enzy mes involved in glucose homeostasis. Therefore, its downregulation resultin g from the E276Q mutation in HNF-4 alpha gene most probably impairs the fun ction of pancreatic beta-cells.