Hepatocyte Nuclear Factor 1 Inactivation Results in Hepatic Dysfunction, Phenylketonuria, and Renal Fanconi Syndrome

Pontoglio, Marco; Barra, Jacqueline; Hadchouel, Michelle; Doyen, Antonia; Kress, Chantal; Bach, Joséphine Poggi; Babinet, Charles; Yaniv, Moshe

doi:10.1016/s0092-8674(00)81033-8

Cited by 548 publications

(526 citation statements)

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“…HNF-1α staining was also detected in the stomach and intestine, but was not detected in the brain and heart. This restricted pattern of HNF-1α staining was compatible with the reported tissue distribution of HNF-1α mRNA [3,4,5,30,31] and β-galactosidase expression of HNF-1α (+/-) mice [6]. Furthermore, HNF-1α immunoreactivity was absent from the nuclei of hepatocytes in HNF-1α (-/-) mice (Fig.…”

Section: Resultssupporting

confidence: 88%

“…Although HNF-1α was initially identified as a hepatocyte-specific transcription factor, it is known also to be expressed in the pancreas [3,4,5,6]. We have found that heterozygous mutations of the HNF-1α gene cause a form of maturity-onset diabetes of the young (MODY3) [7] and clinical studies have shown that MODY3 is characterized by impaired insulin secretion [8,9], suggesting an important role of HNF-1α in pancreatic beta cells.…”

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confidence: 99%

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Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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Aims/hypothesis. One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1α. The pattern of HNF-1α expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1α protein expression in the developing mouse pancreas. Methods. Double immunofluorescence staining was carried out for HNF-1α and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1α mutant mice. Results. HNF-1α was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1α was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1α was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1α on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1α. However, HNF-1α immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1α. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1α (-/-) mice, but expression was markedly decreased in the diabetic stage. Conclusion/interpretation. HNF-1α is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1α might play a role during development. [Diabetologia (2002[Diabetologia ( ) 45:1142[Diabetologia ( -1153

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Section: Resultssupporting

confidence: 88%

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confidence: 99%

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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“…27,54 Fxr and Hnf1a are implicated broadly in cholestatic liver injury. [55][56][57][58] Reports that Sp1 plays a role in liver injury are more anecdotal. [59][60][61] To confirm the role of these four factors, we performed ChIP-seq on liver samples 1 and 14 days after ligation.…”

Section: Resultsmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…HNF-la knockout mice exhibited hepatic dysfunction, phenylketonuria, and Fanconi's syndrome including renal glycosuria, but did not exhibit hyperglycemia (23). Renal glycosuria was also reported in two of the original MODY families described by Tattersall (1) and was a common feature among Finnish MODY3 families examined (M.L.…”

Section: Hnf-la Mutations In Mody3mentioning

confidence: 80%

“…Transcriptional activation of glycolytic genes in hepatocytes is dependent on the action of glucose and insulin (28), so HNF-la might also directly influence liver glucose metabolism. As evidenced by gene knockout studies, HNF-la deficiency disrupts normal hepatic and renal function (23). HNF-la might similarly alter the function of pancreatic (3-cells resulting in impaired insulin secretion.…”

Section: Hnf-la Mutations In Mody3mentioning

confidence: 99%

Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Glucksmann

Lehto²,

Tayber³

et al. 1997

Diabetes

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Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF-la) located on chromosome 12q. We have identified four novel HNF-la missense mutations in M0DY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in M0DY3. We observed no HNFla mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes. Diabetes 46:1081-1086,1997MODY. The MODY1 locus, on chromosome 20q, was shown to be linked in a single extended family (2). M0DY1 was recently shown to be caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF4a) (3). MODY2, located on chromosome 7p (4), is caused by mutations in the glucokinase gene (5). MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8-10), families linked to chromosome 12q are the most frequently described. The glucokinase defects in MODY2 interfere with glucose uptake, resulting in hyperglycemia (5). Although the mechanism of hyperglycemia in MODY1 and MODY3 is not yet understood, phenotypic characterization of these families has shown a deficient insulin secretion response to glucose (11-13).We report here the characterization of the MODY3 gene M region and the results of mutation analysis in eight different aturity-onset diabetes of the young (MODY) is a MODY3 families. We show that MODY3 can be caused by a form of NIDDM with a strong genetic basis, number of different mutations in HNF-la including a mutaDiagnostic criteria for MODY include 1) age of tional hotspot. onset <25 years, 2) correction of fasting hyperglycemia without insulin for at least 2 years, 3) nonketotic RESEARCH DESIGN AND METHODS disease, and 4) autOSOmal dominant mode Of inheritance (1). Family ascertainment and linkage analysis. Families were ascertained based It is therefore expected that a Significant proportion Of MODY on the criteria described by Lehto et al. (13). Genomic DNA was isolated from is caused by Single-gene defects. To date, linkage analysis has P eri P heral blood lymphocytes using standard protocols. Genotyping was pershown that three different, dominant-acting loci can cause fo ™ ed t^^ flu0

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Hepatocyte Nuclear Factor 1 Inactivation Results in Hepatic Dysfunction, Phenylketonuria, and Renal Fanconi Syndrome

Cited by 548 publications

References 40 publications

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

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