scholarly journals Promoter-Specific Repression of Hepatocyte Nuclear Factor (HNF)-1β and HNF-1α Transcriptional Activity by an HNF-1β Missense Mutant Associated with Type 5 Maturity-Onset Diabetes of the Young with Hepatic and Biliary Manifestations

2004 ◽  
Vol 89 (3) ◽  
pp. 1369-1378 ◽  
Author(s):  
Sachiko Kitanaka ◽  
Yuko Miki ◽  
Yasuhide Hayashi ◽  
Takashi Igarashi
Keyword(s):  
Functional Analysis ◽  
Dna Binding ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Repressive Effect

Abstract Mutations in the hepatocyte nuclear factor (HNF)-1β lead to type 5 maturity-onset diabetes of the young (MODY5). HNF-1β forms a homodimer or a heterodimer with HNF-1α and regulates various target genes. HNF-1β mutations are rare, and no functional analysis has been performed in conjunction with HNF-1α. HNF-1β is expressed in the liver and biliary system and controls liver-specific and bile acid-related genes. Moreover, liver-specific Hnf-1β knockout mice present with severe jaundice. However, no patients with HNF-1β mutations have biliary manifestations. In this report, we found a novel missense mutation in the HNF-1β gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5. Functional analysis revealed that the mutant HNF-1β had diminished transcriptional activity by loss of the DNA binding activity. The mutant had a promoter-specific dominant-negative transcriptional effect on wild-type HNF-1β and inhibited its DNA binding. Moreover, the mutant had a promoter- and cell-specific transcriptional repressive effect on HNF-1α and a promoter-specific inhibitory effect on HNF-1α DNA binding. From these results, we considered that the different phenotype of patients with HNF-1β mutations might be caused by the different HNF-1β activity in conjunction with the different repression of HNF-1α activity in selected promoters and tissues.

scholarly journals The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4α activities and introduces a PKA phosphorylation site in its DNA-binding domain

2004 ◽  
Vol 383 (3) ◽  
pp. 573-580 ◽  
Author(s):  
Bénédicte OXOMBRE ◽  
Mostafa KOUACH ◽  
Ericka MOERMAN ◽  
Pierre FORMSTECHER ◽  
Bernard LAINE
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Transcriptional Activity ◽  
Phosphorylation Site ◽  
Binding Domain ◽  
Nuclear Factor ◽  
Dna Binding Domain ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

HNF4α (hepatocyte nuclear factor 4α) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic β-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4α gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115→Ser) HNF4α mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4α-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic β-cell lines, this mutation resulted in strong impairments of HNF4α transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1α, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115→Glu) mutation mimicking phosphorylation reduced HNF4α DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4α function.

scholarly journals Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

2006 ◽  
Vol 190 (1) ◽  
pp. 171-181 ◽  
Author(s):  
Hannah J Welters ◽  
Sabine Senkel ◽  
Ludger Klein-Hitpass ◽  
Silke Erdmann ◽  
Heike Thomas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Onset Diabetes ◽  
Conditional Expression

Mutations in the gene encoding hepatocyte nuclear factor (HNF)1β result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing β-cell mass. The functional role of HNF1β in normal β-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1β, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic β-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1β was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1β also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent β-cells are sensitive to increased expression of WT HNF1β and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

scholarly journals A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Diabetologia ◽  
1997 ◽  
Vol 40 (7) ◽  
pp. 859-862 ◽  
Author(s):  
M. P. Bulman ◽  
M. J. Dronsfield ◽  
T. Frayling ◽  
M. Appleton ◽  
S. C. Bain ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Hepatocyte Nuclear Factor 4 ◽  
Alpha Gene

Mutations in hepatocyte nuclear factor 1beta are not a common cause of maturity-onset diabetes of the young in the U.K

Diabetes ◽  
1998 ◽  
Vol 47 (7) ◽  
pp. 1152-1154 ◽  
Author(s):  
F. Beards ◽  
T. Frayling ◽  
M. Bulman ◽  
Y. Horikawa ◽  
L. Allen ◽  
...  
Keyword(s):  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Common Cause ◽  
Onset Diabetes

scholarly journals Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus

2018 ◽  
Vol 90 (4) ◽  
pp. 257-265 ◽  
Author(s):  
Elif Ozsu ◽  
Filiz Mine Cizmecioglu ◽  
Gul Yesiltepe Mutlu ◽  
Aysegul Bute Yuksel ◽  
Mursel Calıskan ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Rare Condition ◽  
High Sensitivity ◽  
Genetic Mutation ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Turkish Children ◽  
Onset Diabetes

Background/Aims: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. Methods: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. Results: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30–21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. Conclusion: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.

scholarly journals Clinical Application of 1,5-Anhydroglucitol Measurements in Patients with Hepatocyte Nuclear Factor-1  Maturity-Onset Diabetes of the Young

Diabetes Care ◽  
2008 ◽  
Vol 31 (8) ◽  
pp. 1496-1501 ◽  
Author(s):  
J. Skupien ◽  
S. Gorczynska-Kosiorz ◽  
T. Klupa ◽  
K. Wanic ◽  
E. A. Button ◽  
...  
Keyword(s):  
Clinical Application ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Nuclear Factor 1
Sign in / Sign up

Export Citation Format

Share Document