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CREBBP
CREB binding lysine acetyltransferase
The CREBBP gene provides instructions for the CREB binding protein, which is crucial for gene regulation, cellular growth, differentiation, and brain development. The CREBBP gene encodes the CREB binding protein (CBP), a key regulator of gene activity across various tissues in the body.
CREBBP is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Overview
The CREBBP gene is responsible for producing the CREB binding protein, often referred to as CBP. This protein functions as a critical regulator of gene expression throughout the body, influencing processes such as cell growth, division, and differentiation. Normal development before and after birth, particularly brain development and the formation of long-term memories, relies on the proper function of CBP.
What the gene does
The CREB binding protein (CBP) is a multi-functional protein that regulates gene activity through several mechanisms. One primary function is its role as a histone acetyltransferase. CBP attaches acetyl groups to histones, which are structural proteins that help package DNA into chromosomes. This acetylation process alters the chromosome's structure, making specific genes more accessible for transcription, the initial step in protein production. Additionally, CBP acts as a transcriptional coactivator, bridging other proteins (transcription factors) that initiate transcription with the machinery that carries it out. This dual role ensures that genes are appropriately turned on, influencing a wide range of cellular processes.
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Chromosome location
The CREBBP gene is situated on the short arm of chromosome 16, specifically at position 16p13.3. This genomic location is significant for understanding its role in various genetic conditions and its interaction with other genes.
Protein structure
The CREB binding protein (CBP) is a large protein, 2442 amino acids in length, with a complex domain architecture crucial for its diverse functions. It features several disordered regions, including those at amino acids 1-41, 74-179, 266-290, 794-1083, and 1556-1615. Key functional domains include the TAZ-type 1 Zinc finger (amino acids 347-433), the KIX domain (amino acids 587-666), and the Bromo domain (amino acids 1085-1192). The protein also contains a CBP/p300-type HAT domain (amino acids 1323-1700), responsible for its histone acetyltransferase activity, and a ZZ-type Zinc finger (amino acids 1702-1750). Interaction regions with other proteins include those with SRCAP (amino acids 227-410), histone (amino acids 1124-1170 and 1433-1435), ASF1A (amino acids 1162-1180), and TRERF1 (amino acids 1460-1891).
Key variants
Genetic changes, known as variants, in the CREBBP gene can impact the structure and function of the CREB binding protein. These variants can include deletions, insertions, or single nucleotide changes in the DNA sequence. The nature and location of the variant often determine the specific clinical outcomes.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1063C>T | p.Gln355Ter | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome due to CREBBP mutations |
c.1108C>T | p.Arg370Ter | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome due to CREBBP mutations |
c.1237C>T | p.Arg413Ter | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome due to CREBBP mutations |
c.1270C>T | p.Arg424Ter | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome due to CREBBP mutations |
c.1447C>T | p.Arg483Ter | Pathogenic | ★★☆☆ | not provided |
c.1823+5G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | CREBBP-related disorder |
c.223C>T | p.Arg75Ter | Pathogenic | ★★☆☆ | Abnormal cerebral morphology |
c.2302C>T | p.Arg768Ter | Pathogenic | ★★☆☆ | not provided |
c.2881-13G>A | - | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome |
c.3099_3102del | p.Glu1034fs | Pathogenic | ★★☆☆ | Rubinstein-Taybi syndrome due to CREBBP mutations |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the CREBBP gene are primarily associated with Rubinstein-Taybi syndrome, an inherited condition characterised by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. While some features may overlap, variants in CREBBP can also lead to other conditions, such as Menke-Hennekam syndrome, which shares intellectual disability and growth delays but lacks the specific facial and limb abnormalities of Rubinstein-Taybi syndrome. Additionally, somatic (non-inherited) genetic changes involving CREBBP have been linked to certain cancers.
Inheritance pattern
Conditions caused by pathogenic CREBBP variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The CREBBP gene is included in several NHS Genomic Medicine Service national test panels, indicating its recognised clinical significance within the UK. It is a 'green' gene on panels for Developmental Disorders (DDG2P), Early onset or syndromic epilepsy, Foetal anomalies (R21), Glaucoma (developmental), Intellectual disability, IUGR and IGF abnormalities, Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Severe microcephaly (R88), Skeletal dysplasia (R104), and Structural eye disease (R36).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the CREBBP gene?
The CREBBP gene provides instructions for the CREB binding protein, which regulates the activity of many genes. It functions as a histone acetyltransferase, modifying DNA packaging, and as a transcriptional coactivator, linking regulatory proteins to the gene expression machinery.
What conditions are associated with variants in the CREBBP gene?
Variants in the CREBBP gene are most commonly associated with Rubinstein-Taybi syndrome. They can also contribute to Menke-Hennekam syndrome and, in somatic forms, to certain types of cancer.
How does CREBBP affect development?
The CREB binding protein is critical for normal development both before and after birth. It is particularly important for brain development, cellular growth, and the differentiation of cells into specialised types, influencing processes like memory formation.
References
- Banka S, Sayer R, Breen C. Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP. American journal of medical genetics. Part A. 2019. PMID: 30892814
- Menke LA, DDD study, Gardeitchik T. Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome. American journal of medical genetics. Part A. 2018. PMID: 29460469
- Zhang J, Vlasevska S, Wells VA. The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma. Cancer discovery. 2017. PMID: 28069569
- Rusconi D, Negri G, Colapietro P. Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire. Human genetics. 2015. PMID: 25805166
- Thienpont B, Béna F, Breckpot J. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. Journal of medical genetics. 2010. PMID: 19833603
- Bartsch O, Rasi S, Delicado A. Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome. Human genetics. 2006. PMID: 16783566
- Hallam TM, Bourtchouladze R. Rubinstein-Taybi syndrome: molecular findings and therapeutic approaches to improve cognitive dysfunction. Cellular and molecular life sciences : CMLS. 2006. PMID: 16786226
- Bentivegna A, Milani D, Gervasini C. Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients. BMC medical genetics. 2006. PMID: 17052327
- Roelfsema JH, White SJ, Ariyürek Y. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. American journal of human genetics. 2005. PMID: 15706485
- Ward R, Johnson M, Shridhar V. CBP truncating mutations in ovarian cancer. Journal of medical genetics. 2005. PMID: 15937088
- Bartsch O, Schmidt S, Richter M. DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS. Human genetics. 2005. PMID: 16021471
- Coupry I, Monnet L, Attia AA. Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR. Human mutation. 2004. PMID: 14974086
- Rozman M, Camós M, Colomer D. Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation. Genes, chromosomes & cancer. 2004. PMID: 15101047
- Kalkhoven E, Roelfsema JH, Teunissen H. Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. Human molecular genetics. 2003. PMID: 12566391
- Coupry I, Roudaut C, Stef M. Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. Journal of medical genetics. 2002. PMID: 12070251
- McManus KJ, Hendzel MJ. CBP, a transcriptional coactivator and acetyltransferase. Biochemistry and cell biology = Biochimie et biologie cellulaire. 2001. PMID: 11467739
- Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes & development. 2000. PMID: 10887150
- Adam MP, Bick S, Mirzaa GM. Rubinstein-Taybi Syndrome. 1993. PMID: 20301699