Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro

Diabet. Med. 27, 631–635 (2010) Aims Mutations in HNF4A cause a form of monogenic β‐cell diabetes. We aimed to identify mutations in the pancreas‐specific P2 promoter of HNF4A in families with suspected HNF4A diabetes and to show that they impaired the function of the promoter in vitro. Methods We screened families with a clinical suspicion of HNF4A monogenic β‐cell diabetes for mutations in the HNF4A P2 promoter. We investigated the function of the previously reported HNF4A P2 promoter mutation −192C>G linked to late‐onset diabetes in several families, along with two new segregating mutations, in vitro using a modified luciferase reporter assay system with enhanced sensitivity. Results We identified two novel HNF4A P2 promoter mutations that co‐segregate with diabetes in two families, −136A>G and −169C>T. Both families displayed phenotypes typical of HNF4A monogenic β‐cell diabetes, including at least two affected generations, good response to sulphonylurea treatment and increased birthweight and/or neonatal hypoglycaemia. We show that both of these novel mutations and −192C>G impair the function of the promoter in transient transfection assays. Conclusions Two novel mutations identified here and the previously identified late‐onset diabetes mutation, −192C>G, impair the function of the HNF4A P2 promoter in vitro.