Human Molecular Genetics, 2003, Vol. 12, No. 4 441-450
© 2003 Oxford University Press
Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein–Taybi syndrome
1Department of Molecular Cell Biology and 2Department of Human and Clinical Genetics, MGC Centre for Biomedical Genetics, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands and 3Department of Clinical Genetics and 4Department of Pediatrics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands
Received November 22, 2002; Accepted December 13, 2002
Disruption of one copy of the human CREB binding protein (CBP or CREBBP) gene leads to the Rubinstein–Taybi syndrome (RTS), a developmental disorder characterized by retarded growth and mental functions, broad thumbs, broad big toes and typical facial abnormalities. The CREB binding protein (CBP) is an essential transcriptional coactivator for many different transcription factors. CBP has the intrinsic ability to acetylate histones and other proteins, which is regarded as an important step in transcription activation. In vitro studies have shown that this enzymatic activity critically depends on the integrity of a plant homeodomain (PHD)-type zinc finger in the HAT domain of CBP. We therefore investigated whether PHD finger mutations are present in RTS patients. Mutational analysis of 39 patients revealed eight novel heterozygous mutations in the HAT domain of CBP, one of which alters a conserved PHD finger amino acid (E1278K), while a second mutation deletes exon 22, which encodes the central region of the PHD finger. Functional analysis of these RTS-associated PHD finger mutants showed that they lacked in vitro acetyltransferase activity towards histones and CBP itself and displayed reduced coactivator function for the transcription factor CREB. Importantly, in EBV-transformed lymphoblastoid cells from the exon 22 deletion patient we found 
50% less endogenous CBP HAT activity. These findings therefore underscore the functional importance of the PHD finger in vivo and imply that reduction of CBP HAT activity, as exemplified here by disruption of the PHD finger, is sufficient to cause RTS.
* To whom correspondence should be addressed. Tel: +31 715276048; Fax: +31 715276075; Email: d.j.m.peters{at}lumc.nl.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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