Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta.
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, early-onset, and impaired insulin secretion. The type 3 and type 5 forms of MODY result from mutations in the genes encoding the transcription factor, hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta, respectively. The mechanism by which mutations in one allele of the HNF-1 gene impair pancreatic beta cell function is unclear. We studied the effects of wild-type and four mutant (L12H, R263C, P379fsdelCT, and L584S585fsinsTC) HNF-1alpha, which were identified in Japanese subjects with MODY3 on human insulin gene transcription. Both wild-type (WT) HNF-1alpha and HNF-1beta bound to the oligonucleotide containing the A3 element sequence in the human insulin promoter and transactivated the insulin-luciferase reporter gene by 30- and 31-fold, respectively. In contrast, binding of L12H, R263C and L584S585fsinsTC-HNF-1alpha to the probe was impaired. Transactivation activity by the four mutant HNF-1alpha was reduced (4.3 to 43.3% of WT). These data suggest that the insulin gene is a candidate target gene of HNF-1alpha/HNF-1beta and the impairment of insulin gene transcription by mutations in the HNF-1 gene might be involved in the pathogenesis of MODY.
Okita
K
K
Department of Internal Medicine and Molecular Science, Osaka University, Osaka, Japan.
Yang
Q
Q
Yamagata
K
K
Hangenfeldt
K A
KA
Miyagawa
J
J
Kajimoto
Y
Y
Nakajima
H
H
Namba
M
M
Wollheim
C B
CB
Hanafusa
T
T
Matsuzawa
Y
Y
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics*; D017930:Genes, Reporter; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta