TEK
protein-codingTEK receptor tyrosine kinase, the group of CD molecules|Receptor tyrosine kinases|Fibronectin type III domain containing|Immunoglobulin like domain containing
Gene summary
This gene encodes a receptor that belongs to the protein tyrosine kinase Tie2 family. The encoded protein possesses a unique extracellular region that contains two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin type III repeats. The ligand angiopoietin-1 binds to this receptor and mediates a signaling pathway that functions in embryonic vascular development. Mutations in this gene are associated with inherited venous malformations of the skin and mucous membranes. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]
- VMCM
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~121.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0010842
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0800182
Submitter: ClinGen
The *TEK* gene was first reported in relation to primary congenital glaucoma in 2016, with the publication of ten affected families of diverse ancestries (PMID: 27270174). Affected individuals frequently present at birth or in early childhood, although some families with such cases also include other members with late-onset disease, indicating variable expressivity and incomplete penetrance (PMID: 27270174). Affected individuals present in one or both eyes with increased corneal diameter, corneal edema, increased intraocular pressure, increased cup-to-disc ratio of the optic nerve, and/or Haab striae. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (loss-of-function) was found to be distinct from patients diagnosed with multiple cutaneous and mucosal venous malformations, who similarly exhibit an autosomal dominant mode of inheritance but harbor gain-of-function variants in *TEK* that cluster within the protein kinase domain. In addition, the phenotypic differences between the two groups of cases appeared to represent separate disease entities rather than a single spectrum of disease. Therefore, cases caused by inherited *TEK* variants have been split into two separately-curated disease entities, referred to as primary congenital glaucoma-3E (MONDO:0014998, MIM #617272), and multiple cutaneous and mucosal venous malformations (MONDO:0010842, MIM #600195). In order to acknowledge the broader spectrum of onset and variable expressivity of the ocular disease entity, it is referred to in this curation as *TEK*-related primary glaucoma (MONDO:0800182). Thirteen patient-associated variants have been scored as part of this curation (four nonsense, seven missense, and two disrupting splicing), which have been collectively reported in thirteen probands in three publications (PMID: 27270174, PMID: 33027505, PMID: 34956319). All thirteen probands were heterozygous for their respective variants. The mechanism of pathogenicity appears to be monoallelic loss-of-function, caused by null and/or hypomorphic variants. Patient-associated missense variants exhibited diverse functional defects ranging from reduced autophosphorylation or defective ligand response to decreased expression, stability, or solubility (PMID: 27270174, PMID: 33027505, PMID: 34956319). It is important to note that the penetrance of *TEK* variants appears to be influenced in some cases by the presence of modifier alleles in related genes such as *CYP1B1* (PMID: 28620713), *SVEP1* (PMID: 33027505), and possibly *LTBP2* (PMID: 34956319), consistent with the possibility of digenic inheritance. However, none of the cases included in this curation were reported to harbor a potential modifier allele in another glaucoma-related locus. Segregation evidence was not available in these publications and has not contributed to the scoring of the gene-disease relationship. This gene-disease association is also supported by experimental evidence. *TEK* encodes a receptor tyrosine kinase stimulated by angiopoietin ligands to transduce signals that regulate endothelial cell behavior and the development and maintenance of Schlemm's canal, an endothelial structure responsible for aqueous humor drainage in the eye (PMID: 18425120). This function may be mediated in part through upregulation of the *PROX1* gene, which encodes a downstream effector that positively regulates Schlemm’s canal and lymphatic cell fate (PMID: 28920924). *TEK* is highly expressed in ocular tissues (PMID: 30239781) and within the endothelial cells of Schlemm's canal in particular (PMID: 25051267). Mice with heterozygous disruption of the orthologous gene exhibit defects in Schlemm's canal, hypoplastic trabecular meshwork, impaired aqueous humor outflow, and increased intraocular pressure, (PMID: 27270174, PMID: 28920924), as well as enlargement of the anterior chamber (PMID: 25202984). In summary, *TEK* is definitively associated with *TEK*-related primary glaucoma. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on August 18th, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014998
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010842
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020366
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010842
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014998
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010842
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0000365
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0010842
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Ophthalmologic
Intervention: Cardiovascular; Ophthalmologic
Rationale: In Glaucoma 3, primary congenital, E, individuals can have infant/early-childhood ocular hypertension, and optic neuropathy, resulting in vision loss, aand awareness may allow early diagnosis, surveillance, and management; In Venous malformations, multiple cutaneous and mucosal, some individuals have venous malformations (including vascular neoplasms) within internal organs that could lead to severe sequelae, and cardiac malformations have also been described in a few individuals
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TEK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000459.5. 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 | 1 | 9 | 37 | 13 | 60 | |
| missense | 7 | 15 | 179 | 31 | 7 | 239 |
| nonsense | 10 | 8 | 1 | 19 | ||
| start loss | 0 | |||||
| frameshift | 7 | 16 | 23 | |||
| splice donor/acceptor (+/-2bp) | 4 | 5 | 9 | |||
| Total | 24 | 44 | 194 | 68 | 20 | 350 |
Highest pathogenic variant AF is 0.0000065739305
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000450.3 | 23 | MANE Select | |
| Ensembl | ENSP00000369375.4 | 23 | MANE Select | |
| RefSeq | NP_001277006.2 | 22 | Standard | |
| RefSeq | NP_001277007.2 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tek | Danio rerio | Structure: subintestinal vein Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- HIF-1 signaling pathway - Homo sapiens (human)
- Rap1 signaling pathway - Homo sapiens (human)
- Ras signaling pathway - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
Biological Process
- MAPK cascade
- angiogenesis
- response to hypoxia
- positive regulation of protein phosphorylation
- endothelial cell proliferation
Molecular Function
- protein kinase activity
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
Cellular Component
- stress fiber
- extracellular region
- microtubule organizing center
- actin filament
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380036
- Coding exons
- 23
- Length
- 121035
- Individuals with no LoFs
- 125726
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125737
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.35 | 501 | 593 | 0.844 | 0.0000335 | 7372 |
| Missense (PolyPhen) | 141 | 260.27 | 0.54175 | 3143 | ||
| Synonymous | -3.20 | 278 | 218 | 1.28 | 0.0000129 | 2150 |
| Loss of Function | 6.49 | 5 | 58.6 | 0.0854 | 0.00000316 | 699 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000079 | 0.000079 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}.;
- Disease
- DISEASE: Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19079259, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Somatic mutations of TEK are associated with solitary and multiple sporadic venous malformations. {ECO:0000269|PubMed:19079259}.; DISEASE: Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.; DISEASE: Glaucoma 3, primary congenital, E (GLC3E) [MIM:617272]: An autosomal dominant form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:27270174}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.102
Intolerance Scores
- LoFtool
- 0.0457
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.735
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |