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

Abstract

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.

Confirmation of EP300 gene mutations as a rare cause of Rubinstein–Taybi syndrome

“…The EP300 gene mutation predicts a very mildly truncated protein and does not alter the HAT domain, which elsewhere had been shown to be critical in causing RSTS. 5,6 Based on the location of the EP300 gene mutations 4 (also this study), the relatively large number of single-nucleotide polymorphisms (SNPs; 2.33 per patient), and the observed (although not very striking) phenotypical differences with the EP300 mutations detected so far 4 (also this study), we suggest that mutations in EP300 could be underdiagnosed because they may result in phenotypes different from RSTS. Finally, we identified in EP300 a homozygous sequence variation (c.2053 þ 8T) that was present in all individuals studied and therefore most likely represents the wild-type sequence.…”

“…Both CREBBP and p300 are transcriptional coactivators with a plant homeodomain-type zinc finger and a histone acetyl transferase (HAT) domain facilitating chromatin opening. 5,6 They are involved in the regulation of the expression of numerous genes that are important in embryonic development, cell growth, cellular differentiation, and tumor suppression. 7 -10 Despite many similarities, CREBBP and p300 are involved in slightly different signal-transduction pathways.…”

Sequence variations in CREB1 cosegregate with depressive disorders in women

“…38,39 The more extensive developmental manifiestations of the RubinsteinTaybi syndrome appear to result from mutations or microdeletions in coding regions that physically alter the CBP protein 38 and disrupt its histone acetyltransferase activity. 40,41 In addition to the cAMP signaling pathway, growth factors and stress signals stimulate CREB-mediated transcription by promoting the phosphorylation of CREB, 12 and may also contribute to the molecular cascade that influences the development of Mood Disorders and related conditions. Preclinical studies that explore the functional significance of these CREB1 alleles, and clinical studies that employ individuals who carry these susceptibility alleles, seem likely to advance our understanding of the clinical biology and experimental therapeutics of Mood Disorders.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Among the HATs, CBP/p300 are crucial enzymes in development; mutations and deletions of either enzyme causes Rubinstein-Taybi syndrome, characterized by mental disability, among other features [45]. Several studies have described a role for CBP/p300 in neural development.…”

“…Thus, the specific activation of HAT activity could be useful in pathological situations where a decrease in the levels of these enzymes has been described. One example is the case of the RubinsteinTaybi syndrome that presents a haploinsufficiency in CBP and, in some cases, p300 [45,[209][210][211]. A therapeutic strategy based on CBP/p300 reactivation could be useful, even in the adult, for re-establishing at least some cognitive functions [198,212], particularly for ALS, in which motor neurons present lower quantities of CBP owing to degradation [76].…”