Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences

Ryffel, GU

doi:10.1677/jme.0.0270011

Cited by 243 publications

(216 citation statements)

References 114 publications

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“…More than 200 exonic SNPs and truncating mutations have been identified in the human HNF1A gene and they are distributed throughout all of the 10 exons (Ryffel, 2001;Winckler et al, 2005;Ellard and Colclough, 2006). The HNF1 protein is composed of three major domains, that is, dimerization domain (encoded by exon 1), DNA-binding domain (encoded by exons 2 to 4) and transactivation domain (exons 6 to 10).…”

Section: Discussionmentioning

confidence: 99%

“…The HNF1 protein is composed of three major domains, that is, dimerization domain (encoded by exon 1), DNA-binding domain (encoded by exons 2 to 4) and transactivation domain (exons 6 to 10). It has been investigated that the number of variants located in these domains were similar, but the first two had higher numbers of missense mutations and the third had higher numbers of truncation mutations (Ryffel, 2001;Ellard and Colclough, 2006). In addition, the HNF1A gene encodes for three variant isoforms, which are possibly relevant to the relatively high-mutation occurrences in the first six exons (Bellanné -Chantelot et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The HNF1A gene can first activate transcription of HNF4A through its P2 promoter, and in turn the HNF4A gene triggers the transcription of HNF1A. The HNF1A and HNF1B genes bind -E-mail: mfrothsc@iastate.edu together as a heterodimer and then activate numerous genes involved in glucose sensing and insulin secretion (Ryffel, 2001;Rowley et al, 2006;Rhoads and Levitsky, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The mutations in HNF1A are responsible for type 3 MODY (MODY3), a severe form of diabetes, and account for approximately half of the MODY cases (Yamagata et al, 1996b;Ryffel, 2001;Ellard and Colclough, 2006). The HNF1B gene (known as TCF2) is linked to a rare case of type 5 MODY (MODY5), accounting for about 1% of MODY cases and also relevant to other nondiabetic renal diseases (Horikawa et al, 1997;Ryffel, 2001). The HNF4A gene (known as TCF14) is a member of the steroid-thyroid hormone receptor superfamily and it interacts with regulatory elements in promoters and enhancers of the genes involved in cholesterol fatty acid and glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…The HNF4A gene (known as TCF14) is a member of the steroid-thyroid hormone receptor superfamily and it interacts with regulatory elements in promoters and enhancers of the genes involved in cholesterol fatty acid and glucose metabolism. The mutations in the HFN4A gene result in type 1 MODY (MODY1) that could explain 5% of MODY cases (Yamagata et al, 1996a;Ryffel, 2001;Ellard and Colclough, 2006).…”

Section: Introductionmentioning

confidence: 99%

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The Hepatocyte nuclear factor-1 alpha (HNF1A) gene is associated with fatness and loin muscle area in the pig

Fan

Rothschild

2010

Animal

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The significance of hepatocyte nuclear factors (HNFs) in b-cell development and function has been generally recognized in humans, as evidenced by their associations with cases of maturity onset diabetes of the young (MODY). Common Hepatocyte nuclear factor-1 alpha (HNF1A), Hepatocyte nuclear factor-1 beta ( HNF1B) and Hepatocyte nuclear factor-4 alpha ( HNF4A) mutations could lead to monogenic forms 3, 5 and 1 of diabetes mellitus, respectively, and were characterized by MODY in humans. In this study, multiple variants were discovered in the porcine HNF1A and HNF4A genes, and one single-nucleotide polymorphism (SNP) was detected in the HNF1B gene. Using the Iowa State University Berkshire 3 Yorkshire pig resource population, the HNF1A, HNF1B and HNF4A genes were mapped on chromosomes 14, 12 and 17, respectively. The linkage disequilibrium (LD) analyses indicated that most of the HNF1A variants were not in strong LD with each other; however, nearly all of them were highly significantly ( P , 0.01) associated with loin muscle area (LMA). The SNPs c.327-19G.T and c.1768140_23del were significantly ( P , 0.05) associated with backfat and total lipid percentage, and the latter was also associated with muscle glycogen metabolism measures. Four major haplotypes were observed and the association analyses suggested that haplotype 3 (-CGCGD-, I indicates Insertion and D indicates Deletion) was favorable for reduced backfat, while haplotype 1 (-CACGI-) was unfavorably associated with backfat and LMA. There was no significant interaction effect on backfat among the SNPs c.327-19G.T, c.1768140_23del of the HNF1A gene and c.646C.T of the transcription factor-7-like 2 (TCF7L2) gene. These findings suggest that the HNF1A gene has significant effects on both fatness-and meat production-related traits. No significant associations with production traits with the SNPs from the HNF1B and HNF4A genes were observed in the study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Hepatocyte nuclear factor-1 alpha (HNF1A) gene is associated with fatness and loin muscle area in the pig

Fan

Rothschild

2010

Animal

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β‐Cell Biology of Insulin Secretion

Wollheim¹,

Maechler²

2003

International Textbook of Diabetes Mellitus

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Blood glucose homeostasis critically depends on the precise regulation of insulin secretion from the pancreatic β‐cells. The chapter describes how glucose enters the β‐cell, is phosphorylated, and yields metabolic coupling factors mainly in the mitochondria. These factors modify K + and Ca 2+ fluxes across the plasma membrane. It is discussed how cytosolic Ca 2+ triggers exocytosis of the insulin stored in the secretory granules. This process is under tight control of proteins implicated in granule movement, docking, and ultimate fusion with the plasma membrane, resulting in insulin release. Certain β‐cell defects are also illustrated, in particular those linked to mitochondrial dysfunction or mutations in key proteins involved in metabolism–secretion coupling.

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Proteome profiling of tolbutamide‐treated rat primary hepatocytes using nano LC‐MS/MS and label‐free protein quantitation

2012

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Tolbutamide is used as a first line oral antihyperglycemic drug for type 2 diabetes. One side effect of this drug, hepatotoxicity, is well recognized; however, the precise mechanisms underlying tolbutamide-induced hepatotoxicity remain unclear. In this respect, proteomics techniques were used to gain further insight into the mechanistic processes of the hepatotoxicity induced by this drug. In this study, we aimed to identify molecular pathways based on proteins responding to cellular toxicity in tolbutamide-treated primary hepatocytes, using nano UPLC-MS/MS analysis. Rat primary hepatocytes were treated with an IC(20) concentration for 24 h to study the hepatotoxic effects of tolbutamide. For high-throughput label-free quantitation, tryptic-digested peptides of proteins from cell lysates were analyzed using LC-MS/MS and quantitated using the IDEAL-Q software, in which several parameters, such as assisted sequence, elution time, and mass-to-charge ratio were included. We quantified a total of 330 distinct proteins from the tolbutamide-treated hepatocytes and identified 55 upregulated and 82 downregulated proteins with expression changes. Among these differentially expressed proteins, we focused mainly on the 18 upregulated proteins belonging to xenobiotic cytochrome P450 (CYP), drug metabolism/detoxification, oxidative stress/antioxidant response, and cell damage pathway. CYP2D1, CYP2C11, UDP-glucuronosyltransferase 2B (UGT2B), superoxide dismutase 2 (SOD2), 60 kDa heat shock protein (HSPD1), heat shock protein 90 (HSP90), and catalase (CAT) were confirmed by Western blot analysis. In addition, various xenobiotic CYP proteins upregulated in the tolbutamide-treated group, CYP2D1, CYP2C13, and CYP2C11 were confirmed by reverse transcriptase-PCR analysis. Our results offer important new insights into the molecular mechanisms of tolbutamide-induced hepatotoxicity.

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Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences

Cited by 243 publications

References 114 publications

The Hepatocyte nuclear factor-1 alpha (HNF1A) gene is associated with fatness and loin muscle area in the pig

The Hepatocyte nuclear factor-1 alpha (HNF1A) gene is associated with fatness and loin muscle area in the pig

β‐Cell Biology of Insulin Secretion

Proteome profiling of tolbutamide‐treated rat primary hepatocytes using nano LC‐MS/MS and label‐free protein quantitation

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