[PMC free article] [PubMed] [Google Scholar]Servillo G, Della Fazia MA, Sassone-Corsi P. treat RTS. gene can cause Rubinstein-Taybi syndrome (RTS). a scheme illustrates mutations of KIX domain name, herb homeodomain (PHD)-type zinc finger domain name, and histone acetyltransferase (HAT) domain name in CBP protein that are found in patients with RTS. CH1, the first cysteine/histidine rich region (also known as TAZ1); KIX, CREB and MYB conversation domain name, BD, bromo domain name; CH3, the third cysteine/histidine rich region (also known as TAZ2); p160, p160 binding site; TAD, transactivation domain name. b CBP dysfunction due to its mutations leads to epigenetic modification. CBP harbors intrinsic HAT domain and provides functional HAT activity. Mutations and deletions of CBP HAT domain name decrease acetylation of histones, close the chromatin structure, and impair gene expression. In addition, CBP is usually a transcriptional coactivator. The mutation of KIX domain name can prevent conversation of Auristatin F CBP with the cAMP response element (CRE) binding protein (CREB) and other DNA-binding transcription factors and consequently deregulates initiation of gene transcription through the RNA polymerase II complex. In addition, deregulation of CBP function decreases acetylation of UBF and UBF-mediated ribosomal DNA (rDNA) transcription. Heterozygous germ line mutations of the CBP/CREBBP located on chromosome 16p13.3 are associated with RTS majority of the time (50%). Up to this point, specific CBP/CREBBP mutations have been detected in 41% of patients (Caglayan et al. 2011; Coupry et al. 2004; Hennekam et al. 1993; Hennekam 2006). Unsurprisingly, CBP/CREBBP mutations are quite heterogeneous and 92 different mutations have been identified in the HAT (histone acetyltransferase) and KIX domains (consisting of 13 missense, 20 nonsense substitutions, 10 splicing substitutions, 16 small deletions, 2 small indels, 19 gross deletions, 9 small insertions, 1 gross insertion, and 2 complex Auristatin F rearrangements) by the Human Gene Mutation Database (www.hgmd.org) (Fig. 1a) (Bartholdi et al. 2007; Bartch et al. 1999; Blough et al. 2000; Coupry et al. 2002; Coupry et al. 2004; Demeer et al. 2013; Hou 2005; Wallerstein et al. 1997). A much smaller percentage of these mutations are due to CBP/CREBBP homologue EP300 (E1A binding protein p300) on chromosome 22q13.2, while the rest of the cases remain unaccounted for (Hallam and Bourtchouladze 2006). However, new mutations in CBP are being reported as recent as this year (Suzuki et al. 2013). Given that molecular mutations of CBP/CREBBP and p300 only account for half of all of the observed phenotypic features in RTS, it is possible that other epigenetic mechanisms affecting histone acetylation and subsequently gene transcription also contribute to the development of RTS. Therefore, this review paper seeks to summarize currently known epidemiology, diagnosis, treatment, and epigenetic pathophysiology behind RTS and suggest a new mechanism involving p53, microRNAs and CBP/CREBBP/p300. Clinical Features/Diagnostic Methods Several classic clinical facial and limb characteristics are associated with RTS. Facial features include high arched eyebrows, down-slanting palpebral fissures, and broad nasal bridge. Special attention must be given to facial expression, as grimace, or an extraordinary smile with closing of the eyes is almost always observed. Most common limb abnormalities include broad thumbs and broad big toes. Partial duplication of digits, deviation of thumbs and halluces, terminal broadening of phalanges, and fingers may all be present. Growth delays during infancy followed by excessive weight gain in childhood are common, accompanied by global mental retardation and IQs ranging from 25 to 79 with cognitive delay (Balci et al. 2004; Beluffi et al. 1987;Kumar et al. 2012) Special attention is also mandated for internal organ anomalies including heart malformations, such as PDA (patent ductus arteriosus) or atrial/ventricular septal defects, kidney abnormalities, and hypospadias (male urethra birth defect involving an abnormally placed urinary opening on the underside of the penis). Secondary risk seizures may occur, the mechanism of which can be postulated from the fact that changes in the state of chromatin can affect the expression of specific genes involved in the seizure, as exhibited in epilepsy Auristatin F (Urdinguio et al. 2009). Screening and maintenance should be carried out according to current medical Rabbit polyclonal to CDKN2A guidelines. For instance, regardless of the age at diagnosis, an evaluation by a pediatric geneticist knowledgeable in dysmorphology and development, an ECG (electrocardiogram) and an echocardiogram and examination by pediatric cardiologist, a full opthalmologic exam by a pediatric opthamologist, a renal ultrasound and possible VCUG (voiding cystourethrogram) and hearing evaluation, are all required as baseline studies (Wiley et al. 2003). Notably, RTS patients Auristatin F are predisposed to tumors of the brain, meningioma, leukemia, as well as tumors of neural or developmental origins (neuroblastoma, medulloblastoma, rhabdomyosarcomaetc) but with normal life expectancy (Miller and Rubinstein 1995). While no official diagnostic criteria for RTS exists, examining for key clinical features through meticulous history taking and physical exam (head & neck, dental inspection, skin exam.