KLF2
protein-codingKLF transcription factor 2, the group of Kruppel like factors|Zinc fingers C2H2-type
Gene summary
This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is expressed early in mammalian development and is found in many different cell types. The protein acts to bind the CACCC box found in the promoter of target genes to activate their transcription. It plays a role in many processes during development and disease including adipogenesis, embryonic erythropoiesis, epithelial integrity, inflammation and t-cell viability. [provided by RefSeq, Mar 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
*KLF2* was first reported in relation to Pulmonary Arterial Hypertension in 2017 (Eichstaedt et al., PMID: 28188237). Pulmonary Arterial Hypertension is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. Summary of Genetic Evidence: One missense variant has been reported in one proband and her affected sister (PMID: 28188237). The mechanism of pathogenicity appears to be loss of function. Summary of Experimental Evidence: This gene-disease association is supported by expression studies, protein interaction studies, biochemical function studies, and studies analyzing functional alteration in patient cells (PMID: 7565748, PMID: 10458913, PMID: 15136591, PMID: 32132543). The first expression study (PMID: 7565748 and PMID: 10458913), showed *KLF2* expressed in both the mouse and a human lung. The next paper (PMID: 15136591), included both a biochemical function experiment and a protein interaction experiment. The biochemical function experiment demonstrated that overexpression of p300 was able to rescue *KLF2*-mediated inhibition of the NF-B concatemer and augmented *KLF2* induction of the eNOS promoter. The protein interaction experiment demonstrated that *KLF2* induction of the eNOS promoter is dependent on DNA binding. The next paper included analysis of functional alteration in patient cells (PMID: 32132543). The functional alteration experiment demonstrated that HPAH patients with c-terminal (p.H288Y) *KLF2* mutation showed a marked up-regulation of Notch4 and ETS-1 in the remodeled pulmonary vasculature, identified by endothelial vWF and a prominent α-SMA staining in the small, normally non-muscularized arterioles. Although we do have 3 points from the experimental evidence category, the maximum points allowed in the functional category (2) has been reached, and this category will therfore receive 2.5 points, as shown in the classifcation summary. In summary, *KLF2*’s association with autosomal dominant pulmonary arterial hypertension is limited. The classification was approved by the PH GCEP on 8/30/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KLF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016270.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 8 | ||||
| missense | 53 | 1 | 54 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 1 | 57 | 9 | 0 | 67 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057354.1 | 3 | MANE Select | |
| Ensembl | ENSP00000248071.5 | 3 | MANE Select | |
| Ensembl | ENSP00000465035.1 | 2 | Standard | |
| Ensembl | ENSP00000465035.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| klf2b | Danio rerio | Structure: margin Quality: differentiated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- FoxO signaling pathway - Homo sapiens (human)
- Apelin signaling pathway - Homo sapiens (human)
- Fluid shear stress and atherosclerosis - Homo sapiens (human)
- White fat cell differentiation
- EV release from cardiac cells and their functional effects
Biological Process
- negative regulation of transcription by RNA polymerase II
- cell morphogenesis
- in utero embryonic development
- regulation of transcription by RNA polymerase II
- negative regulation of interleukin-6 production
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
- protein binding
- metal ion binding
Cellular Component
- nuclear chromatin
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000248071
- Coding exons
- 3
- Length
- 3058
- Individuals with no LoFs
- 125011
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125012
- p
- 0.00000400
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.21 | 47 | 113 | 0.415 | 0.00000628 | 2147 |
| Missense (PolyPhen) | 3 | 14.781 | 0.20296 | 278 | ||
| Synonymous | -0.486 | 53 | 48.7 | 1.09 | 0.00000275 | 782 |
| Loss of Function | 2.04 | 1 | 6.68 | 0.150 | 3.38e-7 | 93 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000055 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. {ECO:0000269|PubMed:21063504}.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.704
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |