Haemophilia B Leyden arising <i>de novo</i> by point mutation in the putative factor IX promoter region

Royle, Gordon; Water, Neil S. Van De; Berry, Elizabeth W.; Ockelford, Paul; Browett, Peter

doi:10.1111/j.1365-2141.1991.tb07976.x

Cited by 24 publications

(10 citation statements)

References 15 publications

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“…It has been found that promoter mutations in factor IX (4,7,12,19,28,39,45,47,49), protein C (2), haptoglobin (16), and ␤-globin (10,31,(36)(37)(38) lead to disruption of the binding of transcription factors, with a resulting clinically significant reduction of gene expression. Such a lesion might be expected to affect the level of expression of the factor VIII protein and give rise to a clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

McGlynn

Mueller

Begbie

et al. 1996

Molecular and Cellular Biology

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Coagulation factor VIII is an essential cofactor required for normal hemostatic function. A deficiency in factor VIII results in the bleeding disorder hemophilia A. Despite the fact that the factor VIII gene was cloned a decade ago, the mechanisms which control its transcription remain unresolved. In our studies, we have characterized 12 protein binding sites within the factor VIII promoter by DNase I protection assays performed with rat liver nuclear extracts. Three of these elements (sites 1 to 3) are situated within the 5 untranslated region of the gene, while three other sites (sites 4 to 6) lie within the first 100 bp upstream of the transcriptional start site. We have identified an additional site (site 7) ϳ300 bp upstream from site 6, as well as a cluster of five sites in a 250-bp region which terminates ϳ1 kb from the transcriptional start site. Seven of these binding sites (sites 2, 3, 4, 6, 7, 9, and 10) bind members of the C/EBP family of transcription factors. DBP also binds to five of these sites (sites 3, 4, 6, 7, and 9). Utilizing transient transfection studies in HepG2 cells, we have shown that deletion of the factor VIII promoter sequences distal to nucleotide ؊44 results in a significant but small increase in promoter activity. The activity of each of the various 5 deletion constructs is significantly enhanced by cotransfection of C/EBP␣ and D-site-binding protein expression plasmids, while cotransfection of both C/EBP␣ and C/EBP␤ plasmids resulted in a further enhancement of transactivation. These studies also provide evidence of a repressor element located between nucleotides ؊740 and ؊1002. Since the minimal promoter sequence (؊44 to ؉148) maintains the transcriptional activity of the full-length promoter sequence, we proceeded to identify additional factors binding to sites 1 to 4. Competition studies revealed that a ubiquitous transcription factor, NF-Y, binds to site 4, while the liver-enriched transcription factor hepatocyte nuclear factor I (HNF-1) binds to site 1. Mutation analysis of the minimal promoter demonstrated that HNF-1 is critical for activating transcription of the factor VIII gene in vitro. Our results also suggest that the multiple upstream elements that we have identified may act as a backup regulatory region in the event of disruption of the HNF-1 element in the 5 untranslated region.

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Section: Discussionmentioning

confidence: 99%

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

McGlynn

Mueller

Begbie

et al. 1996

Molecular and Cellular Biology

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“…These studies estimate the "r" within the past 150 years, assuming the half-life of a severe X-linked mutation is two generations (Haldane 1935). However, because of small 635 6 Transversions 2 18 c,f 9 Deletions/insertions (<20 bp) e 4 1 b,c 0.25 Deletions (>20 bp) 2 3 1.50 Insertions 0 2 -All mutations 14 47 a Includes germline and somatic origins described herein and in the following references: (Vidaud et al 1986Tanimoto et al 1988;Bottema et al 1989Bottema et al , 1990Koeberl et al 1990;Montandon et al 1990;Royle et al 1991;Taylor et al 1991;Kling et al 1992;Ludwig et al 1992;Thompson et al 1992;Ketterling et al 1993;Knobloch et al 1993;Giannelli et al 1996; Thompson and Chen 1994;Vielhaber et al 1994) b Does not include the following four erroneously reported germline origins in Knobloch et al (1993): Malmö 20 (R-4 W origin ≠MF); Malmö 8 (∆6,398-9, origin ≠MF); Malmö 10 (∆6,666-75, origin ≠MF); Malmö 44 (∆20,398, origin ≠MF); P. Green, personal communication c Includes one somatic mosaic d Includes two somatic mosaics e Includes one family with a combined deletion/insertion f Includes two paternal origins defined in sporadic families with female hemophiliacs g Does not include factor IX Marseille (T-20 C, origin ≠MF) since the germline origin could not be established in the maternal grandfather who was deceased and this mutation is associated with mild disease (Ghanem et al 1993) sample sizes, "r" estimates for specific mutation types have not been attempted in either humans or rodents. Their data consist of point mutation analyses and suggest an overall "male-driven evolution" (an estimated "r" of 6).…”

Section: Potential Biasesmentioning

confidence: 96%

Germline origins in the human F9 gene: frequent G:C→A:T mosaicism and increased mutations with advanced maternal age

Ketterling¹,

Vielhaber²,

Li³

et al. 1999

Human Genetics

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The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (>1 kb), respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P=0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal age was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.

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“…For factor IX, the study of gene expression has been rendered particularly interesting by the existence of the hemophilia B Leyden variants. A detailed molecular characterization of the factor IX gene from patients with the Leyden variant has revealed a number of defects, all clustered within a 33 bp region adjacent to the start site of transcription in the promoter region of the gene [15][16][17][18][19][20][21][22][23]. The Leyden phenotype was initially described in 1970 [14].…”

Section: Spontanous Remission Of Severe Hemophilia B (Fix Leyden)mentioning

confidence: 99%

Clinical significance of gene-diagnosis for defects in coagulation factors and inhibitors

Watzke

2003

Wien Klin Wochenschr

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cDNA sequences of all known coagulation factors and inhibitors of coagulation have been described and an enormous number of disease generating mutations in these factors has been found by genetic analysis of affected families. The vast majority of these defects have severe clinical consequences such as spontaneous bleeding or predisposition to venous thrombosis and pulmonary embolism. While all the genetic defects described so far cause disease, or at least represent a risk factor for diseases such as bleeding or thrombosis, only a minority of these conditions actually need DNA analysis to be detected and/or treated properly. The purpose of this review is therefore to describe clinical situations in which the knowledge of the underlying genetic defect is important for decision making in patients with inherited hemophilia or thrombophilia.

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Haemophilia B Leyden arising de novo by point mutation in the putative factor IX promoter region

Cited by 24 publications

References 15 publications

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

Germline origins in the human F9 gene: frequent G:C→A:T mosaicism and increased mutations with advanced maternal age

Clinical significance of gene-diagnosis for defects in coagulation factors and inhibitors

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