Functional defect of truncated hepatocyte nuclear factor-1alpha (G554fsX556) associated with maturity-onset diabetes of the young

Biochem Biophys Res Commun. 2009 May 22;383(1):68-72. doi: 10.1016/j.bbrc.2009.03.130. Epub 2009 Mar 29.

Abstract

A novel frameshift mutation attributable to 14-nucleotide insertion in hepatocyte nuclear factor-1alpha (HNF-1alpha) encoding a truncated HNF-1alpha (G554fsX556) with 76-amino acid deletion at its carboxyl terminus was identified in a Thai family with maturity-onset diabetes of the young (MODY). The wild-type and mutant HNF-1alpha proteins were expressed by in vitro transcription and translation (TNT) assay and by transfection in HeLa cells. The wild-type and mutant HNF-1alpha could similarly bind to human glucose-transporter 2 (GLUT2) promoter examined by electrophoretic mobility shift assay (EMSA). However, the transactivation activities of mutant HNF-1alpha on human GLUT2 and rat L-type pyruvate kinase (L-PK) promoters in HeLa cells determined by luciferase reporter assay were reduced to approximately 55-60% of the wild-type protein. These results suggested that the functional defect of novel truncated HNF-1alpha (G554fsX556) on the transactivation of its target-gene promoters would account for the beta-cell dysfunction associated with the pathogenesis of MODY.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics*
  • Electrophoretic Mobility Shift Assay
  • Glucose Transporter Type 2 / genetics*
  • HeLa Cells
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Humans
  • Promoter Regions, Genetic
  • Pyruvate Kinase / genetics
  • Rats
  • Sequence Deletion*
  • Transcriptional Activation / genetics*

Substances

  • Glucose Transporter Type 2
  • Hepatocyte Nuclear Factor 1-alpha
  • SLC2A2 protein, human
  • Pyruvate Kinase