Human Molecular Genetics, 2001, Vol. 10, No. 10 1071-1076
© 2001 Oxford University Press
Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein–Taybi syndrome
1Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan, 2Divisions of Cellular and Molecular Medicine and Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA, 3Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA, 4Division of Medical Genetics, Kanagawa Children’s Medical Center, Kanagawa 232-8555, Japan and 5Division of Medical Genetics, Saitama Children’s Medical Center, Saitama 339-0077, Japan
CREB-binding protein (CBP) is a transcriptional coactivator that has intrinsic histone acetyltransferase (HAT) activity. CBP is the causative gene of Rubinstein–Taybi syndrome (RTS). To investigate the relationships between CBP HAT activity and RTS, we analyzed 16 RTS patients. A microdeletion was identified in one patient by fluorescent in situ hybridization analysis. Heteroallelic mutations were identified in five patients by reverse transcriptase–polymerase chain reaction–single-strand conformation polymorphism analysis and sequencing. These included a 2 bp deletion between nucleotides 4319 and 4320, an 11 bp deletion between nucleotides 4898 and 4908, a 14 bp insertion (CCTCGGTCCTGCAC) between nucleotides 5212 and 5213, a 2 bp deletion between nucleotides 5222 and 5223, and a missense mutation from guanine (G) to cytosine (C) at nucleotide 4951 that changed codon 1378 from CGG (arginine) to CCG (proline). The identical missense mutation was introduced into the recombinant mouse CBP. It abolished the HAT activity of CBP and the ability of CBP to transactivate cyclic AMP-response element binding protein (CREB), in HAT assays and in microinjection experiments, respectively. These results suggest that the loss of the HAT activity of CBP may cause RTS, as the first example of a defect of HAT activity in a human disease. Our findings raise the possibility that treatment of RTS patients with histone deacetylase inhibitors might have beneficial effects.
+ To whom correspondence should be addressed. Tel: +81 3 3815 5411; Fax: +81 3 3816 4108; Email: hayashiy-tky@umin.ac.jp
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