The high frequency of the — 6G → A factor IX promoter mutation is the result both of a founder effect and recurrent mutation at a CpG dinucleotide

Morgan, Gareth Edwin; Figueiredo, Margarida Garcia de; Winship, Peter R.; Baker, Ross; Brownlee, G. G.

doi:10.1111/j.1365-2141.1995.tb08388.x

Cited by 13 publications

(8 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12,13 Importantly, the high incidence of this mutation is not simply due to a founder effect, because different haplotypes have been shown to be associated with the À6 mutation. 24 Our assertion that ONECUT proteins operate in vivo predicts that the À7C>T mutation might occur naturally but that it would not have a functional effect on F9 expression, perhaps because it would not disrupt ONECUT binding.…”

mentioning

confidence: 94%

A CpG Mutational Hotspot in a ONECUT Binding Site Accounts for the Prevalent Variant of Hemophilia B Leyden

Funnell

Wilson

Ballester

et al. 2013

The American Journal of Human Genetics

View full text Add to dashboard Cite

Hemophilia B, or the "royal disease," arises from mutations in coagulation factor IX (F9). Mutations within the F9 promoter are associated with a remarkable hemophilia B subtype, termed hemophilia B Leyden, in which symptoms ameliorate after puberty. Mutations at the -5/-6 site (nucleotides -5 and -6 relative to the transcription start site, designated +1) account for the majority of Leyden cases and have been postulated to disrupt the binding of a transcriptional activator, the identity of which has remained elusive for more than 20 years. Here, we show that ONECUT transcription factors (ONECUT1 and ONECUT2) bind to the -5/-6 site. The various hemophilia B Leyden mutations that have been reported in this site inhibit ONECUT binding to varying degrees, which correlate well with their associated clinical severities. In addition, expression of F9 is crucially dependent on ONECUT factors in vivo, and as such, mice deficient in ONECUT1, ONECUT2, or both exhibit depleted levels of F9. Taken together, our findings establish ONECUT transcription factors as the missing hemophilia B Leyden regulators that operate through the -5/-6 site.

show abstract

mentioning

confidence: 94%

A CpG Mutational Hotspot in a ONECUT Binding Site Accounts for the Prevalent Variant of Hemophilia B Leyden

Funnell

Wilson

Ballester

et al. 2013

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…Our series included a young patient (seven years old) with mild HB, who had a well-known nucleotide transition in the F9 promoter region, c.-35G>A (g.-6G>A). This specific mutation has been reported in HB Leiden and predicts a hormonal-dependent increase in factor IX levels after puberty associated with an important improvement in patient's clinical features, normalisation that is predicted to be more significant than for other mutations in this region of the F9 promoter (20,32,33).…”

Section: Nucleotide Mutations In 5' Untranslated Regionsmentioning

confidence: 73%

Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B

Radic¹,

Rossetti²,

Abelleyro³

et al. 2013

Thromb Haemost

View full text Add to dashboard Cite

In Haemophilia B (HB) (factor IX (FIX) deficiency), F9 genotype largely determines clinical phenotype. Aimed to characterise Argentine families with HB, this study presents F9 genotype frequencies and their specific FIX inhibitor risk and 10 novel F9 mutations. Ninety-one DNA samples from HB patients and relatives were subjected to a new scheme: a primary screen for large deletions, a secondary screen for point mutations using conformation sensitive gel electrophoresis, DNA-sequencing and bioinformatic analysis. Our unbiased HB population (N=52)(77% with severe, 11.5% moderate and 11.5% mild HB) showed 32 missense (61.5%) including three novel mutations predicting specific structural/functional defects in silico, 7 nonsense (13.5%)(one novel), 5 large deletions, 4 splice including three novel mutations affecting predicted splicing scores, 3 indels (two novel) and one Leiden mutation. Our comprehensive HB population included five patients with long-lasting FIX inhibitors: three nonsense (p.E35* (novel), p.R75*, p.W240*) and two entire-F9 deletions. A further patient with an indel (p.A26Rfs*14) developed transient inhibitors. A case-control analysis, based on our global prevalence of 3.05% for developing inhibitors in HB revealed that missense mutations were associated with a low risk odds ratio (OR) of 0.05 and a prevalence of 0.39%, whereas nonsense and entire-F9 deletions had significantly higher risks (OR 11.0 and 32.7) and prevalence (14.3% and 44.5%, respectively). Our cost-effective practical approach enabled identification of the causative mutation in all 55 Argentine families with HB, analysis of the molecular pathology of novel F9 defects and determination of mutation-associated FIX inhibitor risks.

show abstract

“…The 62 single nucleotide substitutions included 56 missense mutations, 5 nonsense mutations and a G to A transition at position -6 in the promoter region resulting in an haemophilia B Leyden previously described (16)(17)(18) (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Factor IX Gene Analysis In 70 Unrelated Patients with Haemophilia B: Description of 13 New Mutations

Attali

Vinciguerra²,

Trzeciak³

et al. 1999

Thromb Haemost

View full text Add to dashboard Cite

SummarySeventy unrelated patients suffering from haemophilia B have been screened for determining the molecular defect and for evaluating the spectrum of factor IX mutations in the Rhône Alpes region in France. Most patients were characterized with respect to factor IX antigen and factor IX coagulant activity. We have used denaturing gradient gel electrophoresis to obtain a full scanning of the whole coding, promoter, and exon flanking sequences of the factor IX gene. This technique enabled us to determine the molecular defect in 68 out of 70 families (97%), and the mutation was further identified in the two last patients with a direct sequencing of the gene. A total of 2 complete gene deletions in patients with antifactor IX inhibitor, 6 small insertions/ deletions and 62 point mutations were found. Two of these nucleotide substitutions (Arg145His and Ala233Thr) were detected in 21 patients (30%) suggesting the existence of a local founder effect. Thirteen mutations were previously undescribed, including 7 missense mutations. The detection of mutations in patients affected with haemophilia B may shed some light in the structure-function relationship of factor IX molecule within the coagulation system.

show abstract

The high frequency of the — 6G → A factor IX promoter mutation is the result both of a founder effect and recurrent mutation at a CpG dinucleotide

Cited by 13 publications

References 11 publications

A CpG Mutational Hotspot in a ONECUT Binding Site Accounts for the Prevalent Variant of Hemophilia B Leyden

A CpG Mutational Hotspot in a ONECUT Binding Site Accounts for the Prevalent Variant of Hemophilia B Leyden

Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B

Factor IX Gene Analysis In 70 Unrelated Patients with Haemophilia B: Description of 13 New Mutations

Contact Info

Product

Resources

About