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

CREB-binding protein (CBP) is a transcriptional coactivator that has intrin sic histone acetyltransferase (HAT) activity. CBP is the causative gene of Rubinstein-Taybi syndrome (RTS), To investigate the relationships between C BP HAT activity and RTS, we analyzed 16 RTS patients. A microdeletion was i dentified in one patient by fluorescent in situ hybridization analysis. Het eroallelic mutations were identified in five patients by reverse transcript ase-polymerase chain reaction-single-strand conformation polymorphism analy sis 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 ins ertion (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 (argin ine) to CCG (proline), The identical missense mutation was introduced into the recombinant mouse CBP, It abolished the HAT activity of CBP and the abi lity of CBP to transactivate cyclic AMP-response element binding protein (C REB), 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 findi ngs raise the possibility that treatment of RTS patients with histone deace tylase inhibitors might have beneficial effects.