Hemophilia B Leyden and once mysterious cis-regulatory mutations

•The fraction of known, disease-associated SNPs in regulatory regions is on the rise.•Establishing causality for cis-regulatory mutations is a laborious process.•Saturation mutation mapping has revealed the functional elements of the F9 promoter.•SNPs in regulatory regions can radically alter developmental expression.

Hemophilia B is a classic, monogenic blood clotting disease caused by mutations in the coagulation factor IX (F9) locus. Although interpreting mutations within the gene itself has been relatively straightforward, ascribing molecular mechanisms to the complete suite of mutations within the promoter region has proven somewhat difficult and has only recently been achieved. These mutations, which are clustered at discrete transcription factor binding sites, dynamically alter the developmental expression of F9 in different ways. They illustrate how single-nucleotide mutations in cis-regulatory regions can have drastic ramifications for the control of gene expression and in some instances be causative of disease. Here we present the human F9 promoter as a model example for which saturation mutation mapping has revealed the mechanisms of its regulation. Moreover, we suggest that the growing number of genome-wide studies of transcription factor activity will accelerate both the discovery and understanding of regulatory polymorphisms and mutations.