Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro.
OBJECTIVE
Mutations in HNF4A cause a form of monogenic beta-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 beta-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 beta-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.
Wirsing
A
A
Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
Johnstone
K A
KA
Harries
L W
LW
Ellard
S
S
Ryffel
G U
GU
Stanik
J
J
Gasperikova
D
D
Klimes
I
I
Murphy
R
R
D017668:Age of Onset; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014162:Transfection; D044465:White People / Q000235:genetics
D051557:Hepatocyte Nuclear Factor 4