ArticleAmerican journal of human genetics2013
A CpG mutational hotspot in a ONECUT binding site accounts for the prevalent variant of hemophilia B Leyden.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 30 citations in OpenAlex.
- Identification of NovelJournal of blood medicine · 2025Article
- The Molecular Basis of FIX Deficiency in Hemophilia B.International journal of molecular sciences · 2022Review
- Technologies for profiling the impact of genomic variants on transcription factor binding.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- Conserved regulatory logic at accessible and inaccessible chromatin during the acute inflammatory response in mammals.Nature communications · 2021Article
- Christmas disease in a Hovawart family resembling human hemophilia B Leyden is caused by a single nucleotide deletion in a highly conserved transcription factor binding site of theHaematologica · 2019Article
- First case report of hemophilia B Leyden in Japan.International journal of hematology · 2017Article
- Decreased Transcription Factor Binding Levels Nearby Primate Pseudogenes Suggest Regulatory Degeneration.Molecular biology and evolution · 2016Article
- Hemophilia B: molecular pathogenesis and mutation analysis.Journal of thrombosis and haemostasis : JTH · 2015Review
- MACE: model based analysis of ChIP-exo.Nucleic acids research · 2014Article
- Article
- Computational approaches to interpreting genomic sequence variation.Genome medicine · 2014Article
- Generation of mice deficient in both KLF3/BKLF and KLF8 reveals a genetic interaction and a role for these factors in embryonic globin gene silencing.Molecular and cellular biology · 2013Article
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12 authors at 6 institutions in 4 countries.
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Abstract
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.
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