Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP

Petrif, Fred; Giles, Rachel; Dauwerse, Hans G.; Saris, Jasper J.; Hennekam, Raoul C. M.; Masuno, Mitsuo; Tommerup, Niels; Ommen, G.J.B. van; Goodman, Richard H.; Peters, Dorien J.M.; Breuning, Martijn H.

doi:10.1038/376348a0

Cited by 1,130 publications

(742 citation statements)

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“…The birth prevalence of RSTS is 1:100,000 to 1:125,000 (Hennekam, 2006). RSTS is caused by a heterozygous mutation in the gene encoding the transcriptional co‐activator CREB‐binding protein ( CREBBP ) on chromosome 16p13.3 in about 60% of affected individuals (Petrij et al, 1995), a submicroscopic deletion at 16p13.3 in about 10% of individuals (Hennekam, 2006), or a mutation of the gene E1A binding protein p300 ( EP300 ) on chromosome 22q13.2 in about 5–10% of individuals (Fergelot et al, 2016; Roelfsema et al, 2005). In the remaining RSTS individuals, no specific genetic alterations can be detected and the diagnosis is based on the combination of clinical manifestations only.…”

Section: Introductionmentioning

confidence: 99%

Benign and malignant tumors in Rubinstein–Taybi syndrome

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Overbeek

et al. 2018

American J of Med Genetics Pt A

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Rubinstein–Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (n = 87) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population–based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large‐cell B‐cell lymphoma; breast cancer; non‐small cell lung carcinoma; colon carcinoma). No clear genotype–phenotype correlation became evident. The Dutch population‐based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.

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Section: Introductionmentioning

confidence: 99%

Benign and malignant tumors in Rubinstein–Taybi syndrome

Boot

Belzen

Overbeek

et al. 2018

American J of Med Genetics Pt A

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“…2,3 In human disease, CBP is unique in that it is involved in both leukemogenesis and congenital disease. 4,5 Two different somatic translocations involving the CBP gene are found in acute myelogenous leukemia (AML): the t(8;16)(p11;p13.3) and the t(11;16)(q23;p13.3). 4,[6][7][8][9][10] Moreover, constitutional translocations disrupting the CBP gene lead to the Rubinstein-Taybi syndrome (RTS), a complex developmental disorder that among other symptoms, leads to an increased incidence of neoplasia.…”

Section: Introductionmentioning

confidence: 99%

“…4,[6][7][8][9][10] Moreover, constitutional translocations disrupting the CBP gene lead to the Rubinstein-Taybi syndrome (RTS), a complex developmental disorder that among other symptoms, leads to an increased incidence of neoplasia. 5 Of the two leukemia-associated translocations, the t(8;16) is the more common, with an occurrence of four per 1000 AML patients. 11 Since the first report of the translocation t(8;16) over a decade ago, 12 numerous studies (reviewed by Velloso et al 13 ) have ascertained that this translocation is a recurring cytog-enetic abnormality mainly associated with acute myelogenous leukemia (AML) M4/M5 French-American-British (FAB) subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…Patients frequently show evidence of extramedullary disease and prognosis is relatively poor. 13 We previously identified the CBP gene and that it is disrupted at its 5′ end by the t(8;16), 5 between CBP amino acid residues 188-307. 4 A subsequent independent study confirmed our results and, in addition, showed that the MOZ gene is fused to the CBP gene as a result of the t(8;16).…”

Section: Introductionmentioning

confidence: 99%

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Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16)

et al. 1997

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The CREB-binding protein (CBP) is a large nuclear protein that regulates many signal transduction pathways and is involved in chromatin-mediated transcription. The translocation t(8;16)(p11;p13.3) consistently disrupts two genes: the CBP gene on chromosome band 16p13.3 and the MOZ gene on chromosome band 8p11. Although a fusion of these two genes as a result of the translocation is expected, attempts at detecting the fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR) have proven difficult; to date, only one inframe CBP/MOZ fusion transcript has been reported. We therefore sought other reliable means of detecting CBP rearrangements. We applied fluorescence in situ hybridization (FISH) and Southern blot analyses to a series of AML patients with a t(8;16) and detected DNA rearrangements of both the CBP and the MOZ loci in all cases tested. All six cases examined for CBP rearrangements have breakpoints within a 13 kb breakpoint cluster region at the 5′ end of the CBP gene. Additionally, we used a MOZ cDNA probe to construct a surrounding cosmid contig and detect DNA rearrangements in three t(8;16) cases, all of which display rearrangements within a 6 kb genomic fragment of the MOZ gene. We have thus developed a series of cosmid probes that consistently detect the disruption of the CBP gene in t(8;16) patients. These clones could potentially be used to screen other cancer-associated or congenital translocations involving chromosome band 16p13.3 as well.

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“…Mitochondrial genome (mtDNA) analyses, currently applied to study evolutionary history, population migration, forensic medicine (Pakendorf and Stoneking, 2005) and human disease (O'Brien et al, 2005), have been recently applied to model stem cell turnover rates and clonal evolution in normal tissues; hence was thought to be an ideal tool for this study. Among the nuclear genes, the cyclic AMP response element-binding protein (CREBBP) is involved in multiple cellular processes, functions as a transcriptional cofactor and is also a histone acetyltransferase (HAT) (Petrij et al, 1995). Germline mutations in CREBBP result in RubinsteinTaybi syndrome (Kitabayashi et al, 2001), that is characterized by an increased predisposition to cancer; further validated by the observation that CREBBP þ /À mice express an increased frequency of hematopoietic malignancies (Kung et al, 1999).…”

Section: Introductionmentioning

confidence: 99%