Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome

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...

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Published in:Human molecular genetics Vol. 12; no. 4; p. 441
Main Authors: Kalkhoven, Eric, Roelfsema, Jeroen H, Teunissen, Hans, den Boer, Annemieke, Ariyurek, Yavuz, Zantema, Alt, Breuning, Martijn H, Hennekam, Raoul C M, Peters, Dorien J M
Format: Journal Article
Language:English
Published: England 15.02.2003
Subjects:
Acetyltransferases - metabolism
Amino Acid Motifs
Amino Acid Sequence
Blotting, Western
Chromosome Aberrations
Cyclic AMP Response Element-Binding Protein - genetics
Cyclic AMP Response Element-Binding Protein - metabolism
Exons
Heterozygote
Humans
Models, Genetic
Molecular Sequence Data
Mutation
Plasmids - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Rubinstein-Taybi Syndrome - genetics
Sequence Homology, Amino Acid
Transfection
Tumor Cells, Cultured
ISSN:0964-6906
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Summary: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 approximately 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.
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ISSN:0964-6906
DOI:10.1093/hmg/ddg039