SETBP1 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the SETBP1 gene, its associated disorders, expression patterns, and mutational landscape.
Gene Information Card
| Symbol | SETBP1 |
|---|---|
| Full Name | SET binding protein 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 18q12.3 |
| NCBI Gene ID | 26040 ncbi.nlm.nih.gov/gene/26040 |
| Ensembl ID | ENSG00000152284 |
| UniProt ID | Q9Y6X0 |
| OMIM ID | 611060 |
| HGNC ID | 15573 |
| Aliases | KIAA0436, SEB, MRD29 |
Description
The SETBP1 gene encodes the SET binding protein 1, a large nuclear protein that binds to the SET nuclear oncogene. It is involved in transcriptional regulation, DNA replication, and chromatin remodeling. Mutations in SETBP1 are associated with Schinzel-Giedion syndrome (dominant mutations) and SETBP1 haploinsufficiency disorder (loss-of-function mutations). The gene is also implicated in various cancers, particularly myeloid malignancies, where somatic mutations confer a growth advantage.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Schinzel-Giedion syndrome | De novo heterozygous missense mutations in the SKI/THAP domain (e.g., p.Ile871Ser) cause gain-of-function, leading to increased stability and transcriptional activity of SETBP1, resulting in developmental defects. | OMIM #269150; PMID: 20871602 |
| SETBP1 haploinsufficiency disorder | Loss-of-function mutations (frameshift, nonsense, or deletions) leading to haploinsufficiency cause intellectual disability, speech delay, and distinct facial features. | OMIM #616078; PMID: 25223733 |
| Atypical chronic myeloid leukemia (aCML) | Somatic missense mutations in the SKI/THAP domain (e.g., p.Asp868Asn, p.Gly870Ser) are recurrent and lead to increased SETBP1 protein stability, contributing to leukemogenesis. | COSMIC; PMID: 23269273 |
| Juvenile myelomonocytic leukemia (JMML) | Somatic SETBP1 mutations are found in a subset of JMML cases, often overlapping with RAS pathway mutations, and may confer poor prognosis. | COSMIC; PMID: 23269273 |
| Colorectal cancer | SETBP1 overexpression or mutations have been reported, potentially affecting Wnt signaling and cell proliferation. | COSMIC; PMID: 24651015 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebellum) | 12.4 | Medium |
| Brain (cortex) | 10.8 | Medium |
| Testis | 9.7 | Medium |
| Lung | 6.2 | Low |
| Liver | 4.5 | Low |
| Kidney | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (leukemia) | 15.2 | High expression; relevant to myeloid malignancies |
| HeLa (cervical cancer) | 8.3 | Moderate |
| A549 (lung cancer) | 6.7 | Low |
| MCF7 (breast cancer) | 7.9 | Moderate |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Ile871Ser | Missense | Recurrent in Schinzel-Giedion syndrome | Gain-of-function; increased protein stability |
| p.Asp868Asn | Missense | Recurrent in aCML and JMML | Gain-of-function; increased protein stability |
| p.Gly870Ser | Missense | Recurrent in aCML | Gain-of-function; increased protein stability |
| c.2608C>T (p.Arg870Ter) | Nonsense | Rare in haploinsufficiency disorder | Loss-of-function; haploinsufficiency |
| Whole gene deletion | Copy number variant | Rare in haploinsufficiency disorder | Loss-of-function; haploinsufficiency |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., truncating, deletions) lead to haploinsufficiency, causing SETBP1 haploinsufficiency disorder with intellectual disability and speech delay.
Gain of Function (GOF)
Missense mutations in the SKI/THAP domain (e.g., p.Ile871Ser) are gain-of-function, increasing protein stability and transcriptional activity, leading to Schinzel-Giedion syndrome and contributing to myeloid malignancies.
Dominant Negative (DN)
No evidence for dominant-negative effects; mutations are either gain-of-function or loss-of-function/haploinsufficiency.
View complete mutation data：
Gene Ontology (GO)
| • DNA binding | • protein binding |
| • chromatin binding | • transcription coregulator activity |
| • nucleus | • cytoplasm |
| • regulation of transcription by RNA polymerase II | • cell population proliferation |
| • nervous system development |
Pathways
• Transcriptional regulation by SETBP1
• SETBP1 in myeloid differentiation
• Wnt signaling pathway (via interaction with beta-catenin)
• DNA damage response (via SET complex)
Protein Summary
SETBP1 is a 1,542-amino acid protein with a molecular weight of ~170 kDa. It contains a SKI/THAP domain at the N-terminus, which is critical for DNA binding and protein-protein interactions. The protein binds to SET nuclear oncogene, forming a complex that inhibits protein phosphatase 2A (PP2A), thereby promoting cell proliferation. SETBP1 also interacts with other transcription factors and chromatin remodelers. Mutations in the SKI/THAP domain stabilize the protein, leading to increased PP2A inhibition and oncogenic signaling. In normal tissues, SETBP1 is expressed in the brain, testis, and other tissues, playing roles in development and cell cycle regulation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SETBP1 Knockout HEK293 Cell Line | EDJ-KQ8369 | Human | 26040 | Details Get a Quote |
| SETBP1 Knockout A-549 Cell Line | EDJ-KQ34412 | Human | 26040 | Details Get a Quote |
| SETBP1 Knockout HeLa Cell Line | EDJ-KQ34413 | Human | 26040 | Details Get a Quote |
| SETBP1 Knockout HCT 116 Cell Line | EDJ-KQ72812 | Human | 26040 | Details Get a Quote |
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