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Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP
  1. O Bartsch1,
  2. K Locher2,
  3. P Meinecke3,
  4. W Kress4,
  5. E Seemanová5,
  6. A Wagner1,
  7. K Ostermann2,
  8. G Rödel2
  1. 1Institut für Klinische Genetik, Medizinische Fakultät, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
  2. 2Institut für Genetik, Technische Universität Dresden, 01062 Dresden, Germany
  3. 3Abteilung Medizinische Genetik, Altonaer Kinderkrankenhaus, Bleickenallee 38, 22708 Hamburg, Germany
  4. 4Institut für Humangenetik der Universität, Biozentrum, Am Hubland, 97074 Würzburg, Germany
  5. 5Department of Clinical Genetics, Motol Hospital, 2nd Medical Faculty, Charles University, 15006 Prague 5, Czech Republic
  1. Correspondence to:
 Dr O Bartsch, Institut für Klinische Genetik, Medizinische Fakultät, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany;

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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 …

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