Functional defect of truncated hepatocyte nuclear factor-1alpha (G554fsX556) associated with maturity-onset diabetes of the young.
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.
Kooptiwut
Suwattanee
S
Department of Physiology, Mahidol University, Bangkok, Thailand. S_kooptiwut@hotmail.com
Sujjitjoon
Jatuporn
J
Plengvidhya
Nattachet
N
Boonyasrisawat
Watip
W
Chongjaroen
Nalinee
N
Jungtrakoon
Prapapron
P
Semprasert
Namoiy
N
Furuta
Hiroto
H
Nanjo
Kishio
K
Banchuin
Napatawn
N
Yenchitsomanus
Pa-thai
PT