Rubinstein Taybi Syndrome Essay

Rubinstein-Taybi Syndrome (RTS) is a rare condition characterized by, “distinctive facial features, broad and often angulated thumbs and great toes, short stature, and moderate to severe intellectual disability” (Stevens 2002). The syndrome was first described by Jack Herbert Rubinstein and Hooshang Taybi in the American Journal of Diseases of Children. In their initial article describing their findings, Rubinstein and Taybi described seven children, ages three to eight years old, who presented with “a constellation of congenital anomalies,” which they believed to represent a previously undescribed syndrome (Rubinstein and Taybi 1963). Other features associated with RTS, which tend to vary among affected individuals, include eye abnormalities, defects of the heart and kidneys, dental problems, and obesity (“Genetics Home Reference” 2007). While individuals with RTS often develop normally in-utero, they sometimes fail to thrive in the first few months of life as their height, weight, and head circumference percentiles begin rapidly declining (Stevens 2002). Another serious complication for infants with RBS is

recurrent, life-threatening infections, but few individuals with RTS suffer from this severe form of the disorder (Stevens 2002). More commonly, infants with Rubinstein-Taybi Syndrome must combat respiratory issues and difficulty swallowing due a weakened laryngeal wall, severe constipation, and delayed development (Stevens 2002). Most individuals with RTS live an average lifespan, but some with the most severe form of the condition survive only into early childhood (Park et al. 2014).
Rubinstein-Taybi Syndrome is uncommon – occurring in an estimated 1 in 100,000 to 125,000 newborns (“Genetics Home Reference” 2007). While most affected individuals have a genetic mutation that is responsible for the development of the disorder, about 30% of individuals with RTS have no identified mutation (Fergelot, et al. 2016). In these cases, the cause of the condition is unknown. More often though, the development of Rubinstein-Taybi syndrome is linked to mutations in one of two genes, the CREBBP gene or the EP300 gene (“Genetic Home Reference” 2007).
The CREBBP is located at position 13.3 on the short arm of chromosome 16 and codes for CREB binding protein, which is essential for gene regulation (López, et al. 2016). Some of the roles of CREB binding protein include regulating cell growth and division and prompting cell differentiation. (“Genetics Home Reference” 2007). Most importantly, CREB binding protein appears to be critical for normal prenatal development as well as development after birth (“Genetics Home Reference” 2007). It carries out its function as a transcriptional coactivator – connecting transcription factors with the complex of proteins involved in transcription (Park, et al. 2014). CREB binding protein has histone acetyltransferase (HAT) activity, which allows it to turn genes on or off by modification of the chromatin (Park, et al. 2014). Among many other signaling pathways, CREB binding protein can act as a negative regulator of the cell cycle – preventing the transition from G1 to S phase (“Genetics Home Reference” 2007).
The EP300 gene is located at position 13.2 on the long arm of chromosome 22 (López, et al. 2016). It codes for a protein known as P300 (“Genetics Home Reference” 2007). Like the CREB binding protein, P300 also plays an important role in gene regulation and has found to be critical for normal development before and after birth (“Genetics Home Reference” 2007). It also acts as a transcriptional coactivator and has HAT activity (López, et al. 2016). P300 plays an important role in cell proliferation and differentiation (López, et al. 2016).
While Rubinstein-Taybi Syndrome is classified as an autosomal dominant genetic disorder, most cases result from new mutations and occur in individuals with no family history of RTS (Stevens 2002). Researchers have found a myriad of different variants of mutations in either the CREBBP gene or the EP300 gene that can lead to RTS. In the case of mutation in the CREBBP gene, evidence suggests that RTS is caused by haploinsufficiency of CREB binding protein often resulting from microdeletions (10% of cases) – which are deletions of a very small segment of a chromosome (Stevens 2002). Other mutations that have been shown to cause RTS include frameshift, nonsense, splice site and missense mutations (Stevens 2002). In the case of mutations in the EP300 gene, some mutations that have been shown to cause RTB are chromosomes rearrangements, such as deletions and duplications, and point mutations (López, et al. 2016). Mutations in the EP300 gene are far less researched and appear to be less prevalent than mutations in the CREBBP gene in individuals with Rubinstein-Taybi syndrome (Fergelot, et al. 2016). According to Fergelot, et al., about 60% of cases are caused by mutations in the CREBBP gene, while only 8-10% of cases are known to be caused by mutations in the EP300 gene (2016).
Since both genes are involved in tumor-suppressor pathways, individuals with RTS have an increased risk of developing tumors (both benign and malignant) (Stevens 2002). As a result, leukemia occurs more frequently in people with Rubinstein-Taybi syndrome (Stevens 2002). Individuals with mutations in either of the affected genes tend to present with the same symptoms.
The etiology of Rubinstein-Taybi syndrome is largely unknown, but researchers believe that many of the symptoms associated with RTS may have an epigenetic basis.

It is believed that the loss of CREB binding protein’s acetyltransferase activity is what ultimately leads to RTS (Park et al. 2014). The primary models currently used to explain how mutations in the CREBBP and EP300 genes manifest in the phenotypic features associated with RTS are haploinsufficiency and dominant negative inhibition. In other words, researchers found that two functional copies of the CREBBP gene are necessary to produce normally-functioning CREB binding protein (Park et al. 2014). Additionally, the abnormal protein produced as a result of a mutated CREBBP gene inhibits the normally-functioning CREB binding protein in a process known as dominant negative inhibition (Park et al.

2014).
While CREB binding protein is known to be involved in nearly every stage of development, no specific link to mental retardation has been discovered (Park et al. 2014). One method being proposed to explain how mutations in CREBBP could lead to changes in cognition is related to the fact that CREBBP is activated by signaling pathways in processes like learning and long-term memory (Park et al. 2014). In a study conducted by Oike et al., researchers found mice that were homozygous for a mutation in CREBBP were found to be nonviable, while heterozygous mutant mice were less viable and showed delayed growth and shortened long-term memory (1999). While little is truly known about the correlation between phenotype and genotype in RTS, researchers believe that epigenetic dysregulation plays an integral role (Abel and Zukin 2008).
The diagnosis of Rubinstein-Taybi Syndrome is primarily based on initial assessment of features and patient history (Stevens 2002). Since the features associated with RTS are so distinctive, the diagnosis is typically straightforward. As a result, most individuals do not go through genetic testing. Only when the diagnosis is in question or a patient presents with atypical or very severe features is testing necessary or recommended (Stevens 2002). In these cases, a sequential analysis of CREBBP may be ordered, followed by duplication/deletion analysis if no mutation is found (Stevens 2002). If no mutation is found in CREBBP, sequential analysis and/or deletion/duplication analysis of EP300 may be considered (Stevens 2002).
Following the initial diagnosis, patients are typically evaluated in several ways to fully assess the extent of the condition and each patient’s individual needs. Since RTS affects many different systems, some routine evaluations include: plotting patient’s growth against syndrome-specific growth charts, assessment of development including testing of “gross and fine motor skills, speech/language, cognitive abilities, and vocational skills,” ophthalmologic, auditory, dental and orthodontic evaluations, echocardiogram to evaluate for structural heart defects, renal ultrasound, orthopedic assessment, and evaluation for obstructive sleep apnea if indicated (Stevens 2002). From there, treatment usually addresses the patient’s specific symptoms (ie: standard treatments for eye abnormalities, hearing loss, cardiac defects, and etc. if identified). Developmental disabilities are typically address with early invention programs, special education, and vocation training (Stevens 2002). Patients are often referred to a behavioral specialist or psychologist for behavior management (Stevens 2002).
While most treatment plans for Rubinstein-Taybi Syndrome involve simply treating the symptoms associated with the disorder, researchers Park et al. are investigating the role of epigenetic mechanisms in RTS in an attempt to identify “novel epigenetic biological markers and therapeutic targets to treat RTS” (2014). One treatment option currently being studied is the use of histone deacetylase (HDAC) inhibitors (Park et al. 2014). HDAC inhibitors inhibit transcription removing acetyl groups from lysine and arginine residues (Park et al. 2014). HDAC inhibitors have been shown to improve hippocampal long-term potentiation, or the strengthening of synapses by repeated use (Park et al. 2014). As discussed previously, mice with mutations in their CREBBP gene have deficits in long term memory similar to the cognitive difficulties of those affected by RTS. Treatment of these mutant mice with HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA), has shown to improve deficits in synaptic plasticity and cognition (Abel and Zukin 2008). So far no humans affected by Rubinstein-Taybi Syndrome have been treated with HDAC inhibitors but they seem to be a promising up-and-coming treatment possibility.