A CpG mutational hotspot in a ONECUT (HNF6) binding site accounts for the prevalent variant of Hemophilia B Leyden

ABSTRACT: Hemophilia B, or the 'Royal Disease', arises from mutations in the Coagulation Factor IX (F9) gene. Mutations within the F9 promoter are associated with a remarkable form of the disease, termed Hemophilia B Leyden, in which symptoms ameliorate after puberty. Mutations at the -5/-6 site 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 twenty years. Here we show that the ONECUT transcription factors (ONECUT1/HNF6 and ONECUT2/HNF6B) 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 that correlate well with their associated clinical severities. In addition, expression of F9 is crucially dependent on ONECUT factors in vivo and as such, mice that are deficient in either ONECUT1, ONECUT2 or both, exhibit depleted levels of F9. Taken together, our findings establish the ONECUT transcription factors as the missing regulators of Hemophilia B Leyden that operate through the -5/-6 site.

INSTRUMENT(S): Illumina Genome Analyzer II

ORGANISM(S): Mus musculus

SUBMITTER: Alister Funnell 

PROVIDER: E-MTAB-890 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress