CREB Mutation Schematic - Lab Report Example

www.academia-research.com Sumanta Sanyal d: 25/01/07 CREB Mutation Schematic This paper investigates mutations in all domains of "3',5'-Cyclic Adenosine Monophosphate Response Element Binding" (CREB) (Brunetti, A, et al, 2000) transcriptional factor (TF) and its associated protein CBP that may result in Rubinstein-Taybi syndrome (RTS). CREB is a transcription factor that allows regulation of gene expression mediated by cAMP-responsive signaling pathways that plays a key role in gene regulation, cell proliferation and differentiation (Brunetti, A., et al, 2000). Extracellular signals induce ligands to bind to cell membrane receptors and these, in turn, induce second intracellular messengers to relay signals through protein kinase pathways to CREB, which is resident in the nucleus (Euskirchen, G., et al, 2004). The kinase pathways, in essence, induce phosphorylation of a single residue SER133 (Salks Institute, Undated) on CREB to activate it. There is evidence of four such kinase pathways - cAMP-dependent protein kinase, multiple mitogen-activated protein kinases (MAPKs), ribosome S6 kinase and - and calmodulin-dependent kinases (CAMKs) (Euskirchen, G., et al, 2004). The phosphorylated CREB attracts coactivator CREB binding protein (CBP or CREBBP ) which allows the activated phosphorylated CREB to bind to cAMP-responsive element (CRE) sequences on DNA to initiate gene expression (Thiel, G., et al, 2005). CBP coactivator work is often copied by its paralog p300, a highly related transcriptional coactivator protein targeted by the adenoviral oncoprotein E1A (Brody, T.B., 1996). This is still not a very clear process as much has yet to be known about the mechanism by which CBP binds to the phosphorylated CREB and subsequently promotes gene transcription. For gene transcription to take place a polymerase complex must be recruited, it must then be subsequently isomerized and cleared to transcribe the target gene (Kim, J., et al, 2000). There is evidence that the phsophorylated CREB, after binding with CBP, also recruits a RNA(2) polymerase complex to initiate transcription on CRE elements on target genes in various cells and tissues (Kim, J., et al, 2000). There is much that has been cleared in this direction by the research efforts of Kim et al, 2000, yet more has to be done before any definite conclusions can be reached. The paper now focuses on the molecular and genetic identity of CBP so that the next section on possible mutations on the protein can be better understood. Nevertheless, it is noted here that CREB activity is triggered off by diverse factors such as growth factors, hormones, neurotransmitters, ion fluxes and stress signals (Euskirchen, G., et al, 2004), all of which help recruit the protein. CBP action is initiated through heterodimerization of basic leucine zipper (bZIP) domains (Euskirchen, G., et al, 2004). Its action via gene transcription is also very diverse and the number of genes it helps express is also >100. Thus, mutations in CREBBP or CREB binding protein have numerous implications. The CREB Binding Protein (CBP or CREBBP) CBP is encoded in DNA sequences on human chromosome 16 at 16p13.3 (CREBBP, GeneCard, 2006). Gene location is from GC16M003716 to GC16M003870. The sequence starts at 3,716,568 bp from p terminal and ends at 3,870,723 bp from p terminal making up a sequence of size 154,155 bases with a minus strand orientation (CREBBP, GeneCard, 2006). The human CBP is made up of 2442 amino acid sequences and is 265337 Daltons in molecular weight (CREBBP, GeneCard, 2006). A rough domain count of the protein sequences is available for isoform 'a'. These are as per Table 1 and Diagram 1, Appendix, sourced from Giles et al, 1997, Fig. 3 and 4 respectively. As can be observed from both the table and the diagram, there are 11 distinct domains. This is not exhaustive as there are many regions on the total CREBBP (human) DNA sequence that have not been mapped according to function or even structure (Coupry et al, 2002). Coupry et al, 2002, also state that the CBP gene spans 150 kilobases with 31 exons with a cDNA 9 kb in length. It is noted here that while there are many specific papers that construe functional as well as structural characteristics of the various CBP domains it is not considered essential to do so for this particular paper. Euskirchen et al, 2004, state that CREBBP is stimulated by diverse hormonal action and is highly involved in neuronal function and development. Thus, there are many genes expressed by CREB when bound to protein and it is assumed for the purpose of this paper that the mutations found in RTS patients in the CREBBP genomic sequence region spread across domains that pathologically induce the disorder. Other details on CREBBP have been eschewed. They may be available from the GeneCard, 2006. Instead, the paper shifts focus to mutations in CREBBP that cause the Rubinstein-Taybi syndrome (RTS). RTS Mutations Rubinstein-Taybi Syndrome is a rare congenital disorder that is caused by chromosomal rearrangements and point mutations in one copy of the CREB binding protein on chromosome 16p13.3. It is characterized by "mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors (Bentivegna, A., et al, 2006). The prevalence of the disorder has been estimated to be 1 in 100,000 to 1,25,000 live births (Petrij et al, 2000). Bentivegna et al, 2006, conducted mutation analysis on 31 Italian patients with RTS and found that a high mutation rate (highest rate recorded so far) of 61.1 % was detectable with a high (highest so far) 16% microdeletion rate. Nevertheless, the relatively low rate of detection of mutations in CREBBP in RTS patients points to a pathogenesis that depends partly upon other mutated genes (Bentivegna, A., et al, 2006). Also, mutations in the HAT (histone acetyltransferase) domain of CREBBP detected in many RTS patients together with mutations in the same domain in p300, a CREBBP paralog, detected in a small number of RTS patients points to the fact that mutations in this domain is directly involved in the prevalence of this disorder (Bentivegna, A., et al, 2006). The paper shall now adopt a strategy that shall investigate how mutations in CREBBP that cause Rubinstein-Taybi Syndrome (RTS) are related across a selective of research projects. It shall try to establish how mutations are evident in particular domains in CREBBP and if there is a definite relationship between the mutations and particular CREBBP domains. Methodology The methodology being adopted for the purpose of the paper is simple. It shall correlated data on CREBBP mutations and domains across a number of chosen research papers. Microdeletions, chromosomal rearrangements and truncations that affect the entire genomic length have not been included. Instead, only missense, nonsense and insertions/deletions as well as splice variants that affect parts of the CREBBP gene's 150 kilobase region have been included and collated domain-wise. The data shall be tabulated and, thereafter, graphs relating percentage mutations per domain against domain shall be plotted. The percentage mutations shall be calculated as follows: Number of mutations in a domain/Number of patients assessed = Percentage mutations per domain (It is noted that the type of mutations may be mentioned but it may not be quantitatively involved in the analysis) Seven research groups with analyses papers on mutations in CREBBP for Rubinstein-Taybi syndrome have been chosen - 1) Petrij, et al, 1995, 2) Murata, et al, 2001, 3) Bentivegna et al, 2006; 4) Coupry et al, 2002, 5) Kalkhoven et al, 2002, 6) Roelfsema, et al, 2005 and 7) Bartsch, et al, 2002. Of these seven, six are general assays that probe all possible domains of the CREBBP gene genomic sequences for RTS mutations. In contrast, Kalkhoven et al, 2002, focus on the HAT domain to prove, specifically, that mutations in the putative plant homeodomain (PHD) zinc finger within the HAT domain of CBP causes RTS. Kalkhoven et al, 2002, state that the TTC (trithorax consensus) finger (PHD finger) figures largely in the enzymatic activity that allows the transcription factor CREB, bound with its associated protein CREBBP, to acetylate histones, an important step in the transcription activity. It is also noted that those of the research groups, four in all, who have analyzed RTS patients for microdeletions have also been considered for study and the rate of microdeletion has been calculated with relative data acquired from the groups' research papers. Other gross mutations like rearrangements and truncations have not been considered as their availability from these papers are too sporadic to merit any possible distinct analysis. Result Though only seven research efforts are used in this analysis all of them are distinct in their deployment of mutations to particular domains in CREBBP. This facilitates the analysis and the unbiased choice of the papers proves that the results are subsequently unbiased. As Tables 2a and 2b, Appendix, show, compared to all the other domains, regions and sites where RTS mutations have become evident, the HAT domain is distinctly more prone to manifest such mutations than any other region on the CREBBP genomic regions. No graph is plotted as the results are distinctly evident. The average mutation rate for the HAT domain for all the seven groups is: 15.52%. This despite the fact that Petrij et al, 1995, have found no mutations in that domain. This figure is high compared to percentage mutations in other domains. This short analysis thus proves that the HAT domain region in the CREBBP genomic sequence is highly implicated in the Rubinstein-Taybi syndrome. It is noted here that, as per Table 2a and 2b, the rate of mutations, less gross anomalies, in the CREBBP genomic region is an overall 34.29%, far above the microdeletion rate at 10.16%. It is also noted that, for groups who analyzed patients for microdeletions and other gross anomalies, the percentage mutations have been calculated on the basis of total patients analyzed, including ones exhibiting such microdeletions and other gross anomalies in the CREBBP region. This is except for Coupry, et al, 2002, for whom the number of patients with microdeletions have been excluded from the total number included for calculating percentage total mutations. Thus, for Coupry, et al, 2002, the 3 patients with microdeletions have been excluded and only 60 patients have been accepted as total number analyzed for mutations. This is in variance to the method applied to the other groups but it is believed that the number with microdeletions - 3 - is too low to cause any significant anomaly in results. As per Table 3, Appendix, Taine, et al, 1998, it is found that microdeletions in RTS patients in the relevant chromosomal region is 11.3% (1998 figure). This recent study shows that the percentage figure for microdeletions is 10.16% as per Table 4, Appendix. This conforms to the estimated research findings of other groups. Truncations and gross rearrangements have not been included for this study as their mention in research papers is too sporadic to be considered. Discussion The CREBBP HAT domain has two distinct regions - the aa 1459-1541 region that is partly conserved in all genomic sequences expressing HAT that has subsequently been assigned to the coenzyme A (CoA) binding site and the aa 1237-1311 PHD finger (TTC finger) region. The entire HAT domain spans exons 20-29. The PHD finger is also known as the leukemia-associated-protein (LAP) finger or trithorax consensus (TTC) finger. It is a characteristic zinc finger with a cis4-his-cis3 motif and is found in all proteins that operate at the chromatin level (Kalkhoven, et al, 2002). Petrij et al, 2000, assign the importance of this PHD region in the HAT domain of CREBBP to its ability to assist a multiple signal transduction and a functionally diverse transcription agent as CREBBP needs it to expose chromatin structures with their powerful histone acetyltransferase activity. It acetylates nucleosomal histones as well as histone son other agents in the progression of its transcription activity (Chan and Thangue, 2001). Furthermore, Polesskeya, et al, 2001, have found that the CREBBP/p300 HAT domain is essential for muscle cell differentiation. Another important feature of the CREBBP HAT domain is that it is neuronally centralized in adult function where it is essential for generation of long-term memory (Korzus, et al, 2004). The full implications of HAT activity and the mechanisms of RTS disorder have not yet been deciphered but it is still possible to state that the HAT domain is highly implicated in RTS. Nevertheless, since CREBBP is implicated in so many gene expressions that there is no possible manner in which it, together with its paralog p300, can be specifically assigned as being the only cause of RTS. This is especially so since, as per this study that shows that together with microdeletions rates, the CREBBP mutation percentage is only about 50% in RTS patients. Nevertheless, there is also possibility of other disorders originating from CREBBP mutations and some of these disorders have been deciphered by researchers but there is still a long way to go before all implications of CREBBP activity, either in function or dysfunction, is fully understood. It is also noted in conclusion that the mutations have been calculated domain-wise for best effort at analysis of causes for RTS because the CREBBP genomic region is diverse and, while a number of mutation types have been found duplicated in patients analyzed by separate research groups, the usual variety of mutations, either by protein sequences or splice sites or any other criteria, is too diverse to enable uniformity in data analysis. It is also noted that if the total mutation percentages for Petrij, et al, 1995, and Kalkhoven et al, 2002, are ignored - Petrij et al, 1195, is an early study and not as comprehensive as subsequent ones and Kalkhoven et al, 2002, only analyzed for the HAT domain mutations - than the average total mutation percentage, less gross anomalies, for the remaining five groups, as per Tables 2a and 2b, is as high as 41.4%. There is a distinct pattern in the total percentage figure that may be studied in extension later on in other subsequent studies. It is hoped that this paper, with a unique result of the HAT domain implication in CREBBP, will allow research on CREBBP mutations related to RTS and other disorders to proceed speedily and successfully. Reference 1. Bartsch, O., et al, Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP, Journal of Medical Genetics, 2002, 39, 496-501. Extracted on 24th January, 2007, from: http://jmg.bmj.com/cgi/content/full/39/7/496#R6 2. Bentivegna, Angela, et al, Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients, BMC Medical Genetics, 7:77. Extracted on 15th January, 2007, from: http://www.biomedcentral.com/1471-2350/7/77 3. Brunetti, Antonio, et al, The 3',5'-Cyclic Adenosine Monophosphate Response Element Binding Protein (CREB) is Functionally Reduced in Human Toxic Thyroid Adenomas, Endocrinology, Vol. 141, No. 2, 722-730, 2000. Extracted on 16th January, 2007, from: http://endo.endojournals.org/cgi/content/full/141/2/722#top 4. Chan, Ho Man, and Thangue, Nicholas B. La, p300/CBP proteins: HATs for transcriptional bridges and scaffolds, Journal of Cell Science, 114, 2363-2373, 2001. Extracted on 17th January, 2007, from: http://jcs.biologists.org/cgi/content/full/114/13/2363#top 5. Coupry, I., et al, Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome, Journal of Medical Genetics, 2002; 39; 415-421. Extracted on 15th January, 2007, from: http://jmg.bmj.com/cgi/reprint/39/6/415 6. Euskirchen, Ghia, et al, CREB Binds to Multiple Loci on Human Chromosome 22, Molecular and Cellular Biology, 2004, p. 3804-3814, Vol. 24, No. 9. Extracted on 15th January, 2007, from: http://mcb.asm.org/cgi/content/full/24/9/3804#top 7. GeneCard for CREBBP GC16M003716, 2006, Weizmann Institute of Science. Extracted on 15th January, 2007, from: 8. Giles, Rachel H., et al, Construction of a 1.2 Contig Surrounding, and Molecular Analysis of, the Human CREB Binding Protein (CBP/CREBBP) Gene on Chromosome 16p13.3, Genomics, 4296-114 (1997). 9. Kalkhoven, Eric, et al, Loss of CBP acetyltransferase activity by PHD finger mutations in Rubenstein-Taybi syndrome, Human Molecular Genetics, 2003, Vol. 12, No. 4, pp. 441-450. Extracted on 15th January, 2007, from: http://hmg.oxfordjournals.org/cgi/content/full/12/4/441#top 10. Kim Jeong-a, et al, Distinct cAMP response element-binding protein (CREB) domains stimulate different steps in a concerted mechanism of transcription activation, Proc, Natl, Acad Sci, 2000, 97 (21); 11292-11296. Extracted on 16th January, 2007, from: http://www.pubmedcentral.nih.gov/botrender.fcgi'blobtype=html&artid=17193 11. Korzus, Edward, et al, CBP Histone Acetyltransferase Activity Is a Critical Component of Memory Consolidation, Neuron, Vol. 42, 961-972, 2004. 12. Murata, Takashi, et al, Defect of histone acetyltransferase activity of the nuclear transcriptional co-activator CBP in Rubinstein-Taybi syndrome, Human Molecular Genetics, 2001, Vol. 10, No. 10, 1071-1076. Extracted on 22nd January, 2007, from: http://hmg.oxfordjournals.org/cgi/content/full/10/10/1071#top 13. Ongoing Projects, The Salk Institute, Undated. Extracted on 17th January, 2007, from: http://www.salk.edu/labs/pbl-m/public_html/salk/projects.html#top 14. Petrij, Fred, et al, Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations, J Med Gen, 2000, 37; 168-176, (March). Extracted on 16th January, 2007, from: http://jmg.bmj.com/cgi/reprint/37/3/168 15. Petrij, Fred, et al, Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP, Nature, Vol. 376, pp. 348-351, 1995. 16. Polesskaya, A., et al, CBP/p300 and muscle differentiation: no HAT, no muscle, EMBO J, 2003, 20 (23); 6816-6825. Extracted on 17th January, 2007, from: http://www.pubmedcentral.nih.gov/botrender.fcgi'blobtype=html&artid=125755#cde654c6 17. Roelfsema, Jeroen H., et al, Genetic Heterogeneity in Rubinstein-Taybi Syndrome: Mutations in both the CBP and EP300 Genes Cause Disease, Am. J. Hum. Gen., 76: 572-580, 2005. Extracted on 22nd January, 2007, from: http://www.journals.uchicago.edu/AJHG/journal/issues/v76n4/41866/41866.html 18. Taine, Laurence, et al, Submicroscopic Deletion of Chromosome 16p13.3 in Patients with Rubinstein-Taybi Syndrome, Am. J. Med. Gen., 78: 267-270, 1998. Appendix Table 1: CREBBP (Human) Domains with Residue Sequences Domain Number Domain Name Residue Sequence 1 Nuclear receptor binding domain Receptor-interacting domain (RID) 1 - 102 1 - 171 2 N-terminal transactivation domain (TAD) 228 - 461 3 1st Cys/His-rich region 363 - 430 4 Creb binding domain (CBD) 452 - 683 5 Bromodomain 1108 - 1170 7 Histone acetyltransferase domain (HAT) 1173 - 1849 6 TTC finger (trithorax consensus) 2nd Cys/His-rich region 1231 - 1312 1199 - 1487 9 E1A binding domain 1620 - 1950 8 Protein kinase A (PKA) phosphorylation site 1771 10 Gln-rich region 1849 - 2409 11 C-terminal transactivation domain 1 (TAD) C-terminal transactivation domain 2 (TAD) 1960 - 2038 2059 - 2158 (The Table has been constructed using data from: Giles et al, 1997, Fig. 3) Diagram 1: The CREBBP (Human) Genomic Positioning on Chromosome 16p13.3 Domain positioning correspond with that given in Table 1. (Source: Giles et al, 1997, Fig. 4) Table 2 a: Research Group Coupry et al, 2002. Bentivegna et al, 2006. Kalkhoven et al, 2002. Roelfsema et al, 2005. Bartsch, et al, 2002. Domain Name Percentage Mutations (%) Percentage Mutations (%) Percentage Mutations (%) Percentage Mutations (%) Percentage Mutations (%) Nuclear receptor binding domain Receptor-interacting domain (RID) 3.33% 3.23% 2.17% 5% N-terminal transactivation domain (TAD) 5% 1st Cys/His-rich region 6.45% 2.17% 15% Creb binding domain (CBD) 3.23% 3.26% 5% Bromodomain 3.23 2.17% TTC finger (trithorax consensus) 2nd Cys/His-rich region 3.23% 6.45% 5.13% 7.69% 2.17% 5.43% Histone acetyltransferase domain (HAT) 10% 9.68% (22.6%) 2.56% (20.51%) 5.43% (16.29%) 10% Protein kinase A (PKA) E1A binding domain 1.67% 3.23% 5.13% 3.26% Gln-rich region 5% C-terminal transactivation domain 1 (TAD) C-terminal transactivation domain 2 (TAD) 3.33% 6.45% 1.09% 2.17% Other Regions 8.33% 5% Total 36.66% 45.19% 20.51% 29.32% 40% 1. Note to the Tables 2a and 2b: For all research results, only those mutations, usually nonsense, missense, deletions/insertions and small rearrangements that can be assigned to particular CREBBP domains have been considered for tabulation. Otherwise, microdeletions, rearrangements and truncations that grossly affect the entire CREBBP gene region and cannot be assigned to any particular domain have been ignored. 2. Note to the Table 2a and 2b: It is notable from Table 1 that the TTC finger (trithorax consensus), 2nd Cys/His-rich region, E1A binding domain and protein kinase A (PKA) phosphorylation site all coincide with the histone acetyltransferase (HAT) domain. Wherever possible, mutation percentages have been assigned to these particular regions within the HAT domain. Note to the Table 3: 1. Coupry et al, 2002, Table 3: 63 patients with RTS were analyzed. 3 microdeletions and 3 gross rearrangements were found by FISH and Southern Blot analyses respectively. These have been ignored for the purpose of study. Only the results of direct sequence analyses have been included. The percentage total of 36.7% for 22 mutations among 60 patients is corroborated approximately by the above tabulated results. Coupry et al, 2002, have assigned domains to their mutations and this has been duplicated in this study. It is noted that, for Coupry et al, 2002, the patients with microdeletions have not been included in the total number of patients analyzed for mutations, as has been done for the other groups. Anomaly in results of this study is not expected to increase substantially enough to annul its validity. 2. Bentivegna et al, 2006, Table 2, analyzed 31 RTS patients of whom 19 proved positive for CREBBP mutations. Of these 5 were microdeletions and these have been precluded from analysis in this paper. The rest of the 14 mutations have been included and spread across domains approximately using data from Giles et al, 1997. The percentage total of heteroallelic mutations approximates the paper data. All mutations in the TTC finger, 2nd Cys/His-rich region and the E!A binding domain have been ascribed to the HAT domain as they are HAT intradomain regions. 3. Kalkhoven et al, 2002, analyzed 39 patients for heteroallelic mutations, specifically in the HAT domain. They did not seek to analyze microdeletions. They found 8 mutations spread across the TTC finger, 2nd Cys/His-rich region and the E1A binding domain, all of which have been ascribed to the HAT domain as per policy of the paper. The percentage mutations approximates that of Kalkhoven et al, 2002, research paper. 4. For Roelfsema et al, 2005, Table 1, 5th column, there have been 27 mutations detected in 92 RTS patients. All these comprised of nonsense, missense (all 5 HAT domain mutations) and deletions/insertions that could be assigned to particular domains. Thus, the tabulated percentage total of 29.32% is close to the estimated total of 29.35% as per the group's paper data. As per the policy of this paper, microdeletions and rearrangements have not been tabulated. Roelfsema et al, 2005, detected 9 microdeletions and 1 singular duplication of exon 1. They note that a duplication that causes a disorder like Rubinstein-Taybi syndrome have been detected before. For this paper, it is found that 2 mutations in the 1st Cys/His-rich region coincide with the N-terminal transactivation domain, as is usual with CREBBP domain. Also, the mutations assigned to the TTC finger, the 2nd Cys/His-rich region and the E1A binding domain are assignable to the HAT domain with which they coincide making up a HAT domain total percentage mutation to 16.29%. 5. For Bartsch, et al, 2002, Table 1, 20 RTS patients were analyzed and 2 had microdeletions (ignored) while 8 had types of mutations that could be assigned as per domain and have been tabulated. For this paper it is notable that the 1st Cys/His-rich region coincides with the N-terminal transactivation domain. Thus, the percentage mutations assigned to the Cys/His-rich region is assignable to the TAD domain. The percentage total of mutations (40%) approximates that of the paper. Table 2 b: Research Group Petrij, et al, 1995. Murata et al, 2001. Domain Name Percentage Mutations (%) Percentage Mutations (%) Nuclear receptor binding domain Receptor-interacting domain (RID) 6.25% N-terminal transactivation domain (TAD) 1st Cys/His-rich region 6.25% Creb binding domain (CBD) Bromodomain 6.25% TTC finger (trithorax consensus) 2nd Cys/His-rich region 25% Histone acetyltransferase domain (HAT) (25%) Protein kinase A (PKA) E1A binding domain Gln-rich region C-terminal transactivation domain 1 (TAD) C-terminal transactivation domain 2 (TAD) Other Regions Total 12.5% 31.25% Note to Table 2b: 1. For Petrij, et al, 1995, only 2 patients out of 16 RTS patients demonstrated mutations in CREBBP gene. The first had a mutation in the nuclear receptor binding domain, precisely in the intradomain receptor interacting domain, while the other had a mutation in the 1st Cys/His-rich region within the N-terminal transactivation domain. The total percentage mutation is as per the paper percentage. 2. For Murata, et al, 2001, Table 1, 16 RTS patients were analyzed and 5 were found with mutations in the CREBBP gene. Of these 1 was in the bromodomain while the rest were in the 2nd Cys/His-rich region within the HAT domain. It is thus noted that 25% of the mutations affect the HAT domain and histone acetyltransferase activity. Murata et al, 2001, detected 1 microdeletion among the 16 patients they analyzed. Table 3: Historical (1993-1998) Percentage Mutations in CREBBP in RTS Patients (Derived: Taine, Laurence, et al, 1998, Table 2). Table 4: Percentage Microdeletions in Analyzed RTS Patients Research Group Percentage Microdeletions Coupry et al, 2002 4.76 Benvetigna et al, 2006 16.1% Roelfsema et al, 2005 9.78% Bartsch et al, 2002 10% Average 10.16% Only those groups that have analyzed for microdeletions have been included. It is notable that Benvetigna et al, 2006, have detected the highest rate of microdeletions among RTS patients so far. Read More