Abstract
Mutations in the hepatocyte nuclear factor 4alpha (HNF-4alpha) gene are associated with one form of maturity-onset diabetes of the young (MODY1). The R154X mutation generates a protein lacking the E-domain which is required for normal HNF-4alpha functions. Since pancreatic beta-cell dysfunction is a feature of MODY1 patients, we compared the functional properties of the R154X mutant in insulin-secreting pancreatic beta-cells and non-beta-cells. The R154X mutation did not affect nuclear localisation in beta-cells and non-beta-cells. However, it did lead to a greater impairment of HNF-4a function in beta-cells compared to non-beta-cells, including a complete loss of transactivation activity and a dominant-negative behaviour. .
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Base Sequence
-
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
-
COS Cells
-
Cell Line
-
Cell Nucleus / metabolism
-
DNA Primers / genetics
-
DNA-Binding Proteins*
-
Diabetes Mellitus, Type 1 / genetics*
-
Diabetes Mellitus, Type 1 / metabolism
-
Hepatocyte Nuclear Factor 4
-
Humans
-
Islets of Langerhans / metabolism
-
Molecular Sequence Data
-
Phosphoproteins / chemistry
-
Phosphoproteins / genetics*
-
Phosphoproteins / metabolism*
-
Point Mutation*
-
Protein Structure, Tertiary
-
Recombinant Fusion Proteins / chemistry
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
Transcription Factors / chemistry
-
Transcription Factors / genetics*
-
Transcription Factors / metabolism*
-
Transcriptional Activation
Substances
-
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
-
DNA Primers
-
DNA-Binding Proteins
-
HNF4A protein, human
-
Hepatocyte Nuclear Factor 4
-
MLX protein, human
-
Phosphoproteins
-
Recombinant Fusion Proteins
-
Transcription Factors