Statistics from Altmetric.com
- RTS, Rubinstein-Taybi syndrome: CREB, cAMP responsive element binding protein
- TAD, transactivation domain
- SNP, single nucleotide polymorphism
- HAT, histone acetyltransferase
The genetic analysis of the Rubinstein-Taybi syndrome (RTS, OMIM 180849) may shed light on mechanisms of transcription, brain function, keloid formation, and cancer.1–6 RTS can be caused by heteroallelic mutations of CREBBP (the gene for cAMP responsive element binding (CREB) binding protein).2 Human CREBBP resides on chromosome 16p13.3,7–9 spans approximately 150 kb at the genomic level, and comprises a coding sequence of 7329 bp.10 The protein (2442 amino acids) is conserved (human v mouse, 94% amino acid identity)10 and a transcriptional coactivator.4–6 Predicted domains include the nuclear receptor binding and receptor interacting domain (aa 1-170), the amino-terminal transactivation domain (N-terminal TAD, aa 228-461), the Cys/His rich region (aa 363-496), the CREB binding domain (aa 452-682), the bromodomain (aa 1108-1170), the histone acetyltransferase domain (aa 1173-1849), the trithorax consensus finger and Cys/His rich region (aa 1232-1487), the E1A oncoprotein binding domain (aa 1679-1732), the protein kinase A phosphorylation site (aa 1771), the Gln rich region (aa 1849-1999), and the C-terminal TAD (aa 1960-2162).10
Mutations of CREBBP reported in RTS have included chromosomal translocations, deletions at the microscopic and submicroscopic level, and molecular mutations.2,7–9,11–14 Apart from a recent report,14 previous studies on RTS used the protein truncation test before molecular analysis, thereby limiting the spectrum of observed molecular mutations. To date, 11 small mutations of CREBBP have been reported, comprising truncating mutations and one missense mutation.2,13,14 Two modes of action of how CREBBP mutations may cause RTS have been discussed, haploinsufficiency and dominant negative effects. The haploinsufficiency mechanism is made likely by the observation that some 10% of subjects with RTS exhibit deletion of one CREBBP allele, and that deletions of different domains of CREBBP were found with the same RTS phenotype, without …
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.