Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse

Bach, Ingolf; Galcheva-Gargova, Zoya; Matteï, Marie‐Geneviève; Simon-Chazottes, Dominique; Guénet, Jean-Louis; Cereghini, S.; Yaniv, Moshe

doi:10.1016/0888-7543(90)90238-p

Cited by 68 publications

(35 citation statements)

References 46 publications

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“…Because in this region, the human TCF1 gene, a biologically plausible candidate gene, has been mapped, 37 we genotyped 10 polymorphisms in the GAIT sample located across this gene (6 in noncoding regions and 4 in coding regions). The measured genotype association analysis revealed significant association with 3 of the SNPs and fibrinogen levels ( Table 2), supporting the presence of a QTL in the region of TCF1 gene.…”

Section: Resultsmentioning

confidence: 99%

“…The peak LOD score occurred between markers D12S79 and D12S1718 in a region 12q24.21 (Figure 3), where the TCF1 gene that encodes the hepatocyte nuclear factor 1 (HNF1), is mapped. 37 The HNF1 binds to a sequence required for hepatocyte-specific transcription of the gene for the ␤-chain of fibrinogen and also interacts with homologous sequences required for optimal promoter function of the genes for the ␣-and ␤-chains of fibrinogen. 45,46 Thus, TCF1 is an obvious candidate gene to explain the observed linkage to the fibrinogen plasma levels.…”

Section: Discussionmentioning

confidence: 99%

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A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels

Soria

Almasy

Souto

et al. 2005

ATVB

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Background— Fibrinogen levels are a widely accepted risk factor for cardiovascular disease, but the extent of the genetic component is unknown. Materials and Results— To search for these genes, we conducted a genome-wide scan using 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophila (GAIT) Project. Two loci were detected: 1 on chromosome 12 and another on chromosome 14. There are no cardiovascular-related candidate genes on chromosome 14, which implies that this locus represents a novel cardiovascular risk factor. Importantly, the locus on chromosome 12 contains the hepatocyte nuclear factors (TCF1), a candidate gene involved in the hepatocyte-specific transcription of the fibrinogen α-chain and β -chain genes. Three polymorphisms in TCF1 showed significant association with fibrinogen levels, supporting the implication of TCF1 in the determination of this phenotype. Conclusions— Two loci , 1 on chromosome 12 (most likely the TCF1 ) and another on chromosome 14, are important determinants of fibrinogen levels in Spanish families. These data should help define the relationship between fibrinogen levels and the risk of cardiovascular disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels

Soria

Almasy

Souto

et al. 2005

ATVB

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“…The HindIII-NsiI segment was derived from a PCR amplification product made with the forward primer 5Ј-GGCA A AGCT TCCATGGT T TCTA A ACTGAGCCAG-3Ј and a reverse primer downstream of the NsiI site at amino acid 241. Thus, the entire ORF of the human HNF1␣ as cloned in HCL16 (20) was linked to the six myc epitope tags. The integrity of the ORFs in all of the expression vectors was verified by sequencing the inserted DNA sequences.…”

Section: Methodsmentioning

confidence: 99%

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Wild

Strandmann

Nastos

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor hepatocyte nuclear factor 1␤ (HNF1␤) is a tissue-specific regulator that also plays an essential role in early development of vertebrates. In humans, four heterozygous mutations in the HNF1␤ gene have been identified that lead to early onset of diabetes and severe primary renal defects. The degree and type of renal defects seem to depend on the specific mutation. We show that the frameshift mutant P328L329fsdelCCTCT associated with nephron agenesis retains its DNA-binding properties and acts as a gain-of-function mutation with increased transactivation potential in transfection experiments. Expression of this mutated factor in the Xenopus embryo leads to defective development and agenesis of the pronephros, the first kidney form of amphibians. Very similar defects are generated by overexpressing in Xenopus the wild-type HNF1␤, which is consistent with the gain-of-function property of the mutant. In contrast, introduction of the human HNF1␤ mutant R137-K161del, which is associated with a reduced number of nephrons with hypertrophy of the remaining ones and which has an impaired DNA binding, shows only a minor effect on pronephros development in Xenopus. Thus, the overexpression of both human mutants has a different effect on renal development in Xenopus, reflecting the variation in renal phenotype seen with these mutations. We conclude that mutations in human HNF1␤ can be functionally characterized in Xenopus. Our findings imply that HNF1␤ not only is an early marker of kidney development but also is functionally involved in morphogenetic events, and these processes can be investigated in lower vertebrates.

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“…20 -22 The HNF1A gene product, HNF-1␣, is a transcriptional activator of several hepatic genes, including albumin, ␣1-antitrypsin, and ␣-and ␤-fibrinogen. 21,22 In addition, HNF-1␣ was shown to enhance transcription of apolipoprotein (apo) B [23][24][25] and apo(a) 26 and to downregulate transcription of apo CIII and apo AI. 27 Because it regulates the transcription of several apolipoprotein genes, it is possible that naturally occurring mutations in HNF-1␣ could affect plasma lipoprotein metabolism.…”

mentioning

confidence: 99%

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

Hegele¹,

Cao²,

Harris³

et al. 2000

ATVB

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Abstract-We previously showed an extremely strong association between type 2 diabetes and a private polymorphism, namely G319S, in the hepatocyte nuclear transcription factor (HNF)-1␣. Because HNF-1␣ is involved in the transcription of several apolipoprotein genes, we tested for an association between the private HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2 diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with lower plasma concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B. In Oji-Cree subjects without type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with higher plasma concentrations of high density lipoprotein cholesterol and apo AI. There were no associations with plasma triglycerides or lipoprotein(a). Regression analysis indicated that the HNF1A genotype accounted for Ϸ10% of the variation in the apo B-related traits in the diabetic subjects and for Ϸ5% of the variation in the apo AI-related traits in the nondiabetic subjects. Furthermore, the regression model indicated that the HNF1A S319 allele affected these traits in a dominant manner in subjects with and without type 2 diabetes. These findings provide the first evidence that a rare variant in a nuclear transcription factor is associated with variation in plasma lipoprotein traits.

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Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse

Cited by 68 publications

References 46 publications

A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels

A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

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