Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome
| العنوان: | Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome |
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| المؤلفون: | A. Zantema, Hans Teunissen, Raoul C.M. Hennekam, Eric Kalkhoven, Jeroen H. Roelfsema, Martijn H. Breuning, Dorien J.M. Peters, Yavuz Ariyurek, Annemieke den Boer |
| المساهمون: | Paediatric Genetics |
| المصدر: | Human molecular genetics, 12(4), 441-450. Oxford University Press |
| بيانات النشر: | Oxford University Press (OUP), 2003. |
| سنة النشر: | 2003 |
| مصطلحات موضوعية: | Heterozygote, Amino Acid Motifs, Blotting, Western, Molecular Sequence Data, education, Biology, Transfection, CREB, medicine.disease_cause, Exon, Acetyltransferases, Coactivator, Tumor Cells, Cultured, Genetics, medicine, Humans, Amino Acid Sequence, CREB-binding protein, Cyclic AMP Response Element-Binding Protein, Molecular Biology, Transcription factor, Genetics (clinical), Chromosome Aberrations, Rubinstein-Taybi Syndrome, Zinc finger, Mutation, Models, Genetic, Sequence Homology, Amino Acid, Reverse Transcriptase Polymerase Chain Reaction, Exons, General Medicine, PHD finger, biology.protein, Plasmids |
| الوصف: | 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. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd113b15409bb69b30fb004b41dba5ecTest https://doi.org/10.1093/hmg/ddg039Test |
| حقوق: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....fd113b15409bb69b30fb004b41dba5ec |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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