Journal Article

Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein–Taybi syndrome

Takashi Murata, Riki Kurokawa, Anna Krones, Ken Tatsumi, Masami Ishii, Tomohiko Taki, Mitsuo Masuno, Hirofumi Ohashi, Masayoshi Yanagisawa, Michael G. Rosenfeld, Christopher K. Glass and Yasuhide Hayashi

in Human Molecular Genetics

Volume 10, issue 10, pages 1071-1076
Published in print May 2001 | ISSN: 0964-6906
Published online May 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.10.1071
Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in  Rubinstein–Taybi syndrome

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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.

Journal Article.  4362 words.  Illustrated.

Subjects: Genetics and Genomics

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