Authors:
APW Funnell, MD Wilson, B Ballester, KS Mak, J Burdach, N Magan, RCM Pearson, FP Lemaigre, KM Stowell, DT Odom, P Flicek, M Crossley
Journal name: 
Am J Hum Genet
Citation info: 
92(3):460-467
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.
DOI: 
http://doi.org/10.1016/j.ajhg.2013.02.003
Research group: 
Odom Group
E-pub date: 
07 Mar 2013