Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

Galán, María; García-Herrero, Carmen-María; Azriel, Sharona; Gargallo, Manuel; Durán, María Rosa; Gorgojo, Juan-Jose; Andía, Victor-Manuel; Navas, María-Ángeles

doi:10.2119/molmed.2010.00097

Cited by 36 publications

(36 citation statements)

References 51 publications

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“…) promoters. The discrepancy between these findings and those of the previous study may be due to the different cell lines used [i.e. mouse pancreatic (Min6) and African green monkey kidney (Cos7) cells, compared with our human hepatoma and intestinal cells].…”

Section: Discussioncontrasting

confidence: 99%

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Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations

et al. 2013

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Objectives. Heterozygous mutations in hepatocyte nuclear factor 1a (HNF1a) cause maturity onset diabetes of the young 3 (MODY3), an autosomal dominant form of diabetes. Deficiency of HNF1a in mice results in diabetes, hypercholesterolaemia and increased bile acid (BA) and cholesterol synthesis. Little is known about alterations in lipid metabolism in patients with MODY3. The aim of this study was to investigate whether patients with MODY3 have altered cholesterol and BA synthesis and intestinal cholesterol absorption. A secondary aim was to investigate the effects of HNF1a mutations on the transcriptional regulation of BA metabolism.Methods. Plasma biomarkers of BA and cholesterol synthesis and intestinal cholesterol absorption were measured in patients with MODY3 (n = 19) and in matched healthy control subjects (n = 15). Cotransfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients.Results. Plasma analysis showed higher levels of BA synthesis in patients with MODY3. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Cotransfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7a-hydroxylase promoter compared with HNF1a, without further differences in other studied promoters. By contrast, the other four mutations (L107I, T260M, P291fsinsC and R131Q) reduced the induction of the farnesoid X receptor (FXR) promoter, which was followed by reduced repression of the small heterodimer partner promoter. In addition, these mutations also reduced the induction of the apical sodium-dependent bile salt transporter promoter.Conclusions. BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1a affect promoters involved in BA metabolism.

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Section: Discussioncontrasting

confidence: 99%

“…P379A is a missense mutation located in the transactivation domain, and it has previously been reported that the transactivation potential is decreased compared with HNF1α . However, we found that this mutation increased the activation of the CYP7A1 promoter compared with HNF1α (Fig.…”

Section: Discussionmentioning

confidence: 51%

Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations

et al. 2013

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“…We determined the effect of Pax6 on HNF4A-P2-Luc in HEK293 and HepG2 cells. We also included HNF1α, which was known to activate the P2 promoter, 30 as a positive control. HNF1α activated HNF4A-P2-Luc by eight-fold and five-fold in HEK293 and HepG2 cells, respectively ( Figure 4B).…”

Section: Pax6 Activates the P2mentioning

confidence: 99%

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Guo

Lü

2018

J of Cellular Biochemistry

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Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver, whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α. HNF4A-AS1, a long noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. Paired box 6 (PAX6), a master regulator of pancreas development overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4α mutants identified in patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer. Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1α and farnesoid X receptor, key regulators of insulin secretion. Taken together, our study provides novel mechanistic insights regarding the transcriptional regulation and transactivation activity of HNF4α in digestive tissues.

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“…Mutations in the HNF1A gene are characterized by a progressive deficiency in glucose-stimulated insulin secretion. The functional analysis of mutations in MODY 3 is useful to identify the corresponding molecular defects that might contribute to unveil the mechanism of b-cell impairment in these patients (Gal an et al 2011). The HNF1A protein is a transcription factor involved in the expression of b-cell genes like pyruvate kinase, GLUT2, and insulin.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes

Magaña-Cerino

Luna-Arias

Labra-Barrios

et al. 2016

Molec Gen & Gen Med

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Background HNF1A gene regulates liver‐specific genes, and genes that have a role in glucose metabolism, transport, and secretion of insulin. HNF1A gene mutations are frequently associated with type 2 diabetes. HNF1A protein has three domains: the dimerization domain, the DNA‐binding domain, and the trans‐activation domain. Some mutations in the dimerization or DNA‐binding domains have no influence on the normal allele, while others have dominant negative effects. The I27L, A98V, and S487N polymorphisms are common variants of the HNF1A gene; they have been found in T2D and non‐diabetic subjects.Methods and ResultsWe searched for mutations in the first three exons of the HNF1A gen in an Amerindian population of 71 diabetic patients. DNA sequencing revealed the previously reported I27L polymorphism (c.79A>C) in 53% of diabetic patients and in 67% of the control group. Thus, the I27L/L27L polymorphism might be a marker of Amerindians. In addition, we found the c.422_423InsT mutation in the HNF1A gene of one patient, which had not been previously reported. This mutation resulted in a frame shift of the open reading frame and a new translation stop in codon 187, leading to a truncated polypeptide of 186 amino acids (Q141Hfs*47). This novel mutation affects the DNA‐binding capacity of the mutant HNF1A protein by EMSA; its intracellular localization by fluorescence and confocal microscopy, and a dominant‐negative effect affecting the DNA‐binding capacity of the normal HNF1A by EMSA. We also studied the homology modeling structure to understand the effect of this mutation on its DNA‐binding capacity and its dominant negative effect.ConclusionThe HNF1A Q141Hfs*47 mutant polypeptide has no DNA‐binding capacity and exerts a dominant negative effect on the HNF1A protein. Therefore, it might produce severe phenotypic effects on the expression levels of a set of β‐cell genes. Consequently, its screening should be included in the genetic analysis of diabetic patients after more functional studies are performed.

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Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

Cited by 36 publications

References 51 publications

Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations

Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes

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