title: Hemophilia B Leyden and once mysterious cis-regulatory mutations.
abstract: 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.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, NSW 2052, Australia.
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, NSW 2052, Australia. Electronic address: m.crossley@unsw.edu.au.
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C064567:factor IX Leyden; D005164:Factor IX
keywords: SNPs; gene regulation; hemophilia; promoter mutations; regulatory mutations