Mutations in CIS-Acting Transcriptional Regulatory Elements

Abstract This and subsequent chapters of Part Two will focus on human diseases that are caused by abnormal structure and/or function of the cis-acting DNA sequences or trans-acting protein factors that represent the two major components of transcriptional systems. Part Two will differ from Part One by the introduction of clinical data into the discussion. In order to provide a resource for further exploration, the description of each clinical condition will include the relevant catalogue (MIM) number in the Online Mendelian Inheritance in Man (OMIM™) database, which can be accessed at the National Center for Biotechnology Information, National Library of Medicine, via the World Wide Web. A less up-to-date hard copy of MIM is also available (McKusick, 1994). The discussion of transcriptional pathophysiology begins with a description of the less common mechanism by which transcription is de ranged, mutations within cis-acting DNA sequences that represent transcription factor binding sites. Binding site mutations may represent a less common cause of transcriptional derangement because of the cooperative nature of DNA binding in which protein-protein interactions between factors binding at adjacent sites (either directly or via interactions with common coactivators) may stabilize DNA binding. Under these circumstances a point mutation might decrease the affinity of a transcription factor for its cognate nucleotide sequence so that the factor could no longer bind to the isolated DNA sequence in vitro, yet might still be capable of binding in vivo.