THPO
protein-codingthrombopoietin, the group of Receptor ligands
Gene summary
Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5' UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent. [provided by RefSeq, Feb 2014]
- MGDF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008554
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008554
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008554
Submitter: Genomics England PanelApp
Inheritance Pattern: SD
Disease ID:MONDO:0800451
Submitter: ClinGen
The *THPO* gene encodes the ligand for *MPL*, thrombopoietin, a hematopoietic growth factor that regulates the development of megakaryocytes and platelets as well as the self-renewal of hematopoietic stem cells. LUMPING AND SPLITTING CONSIDERATIONS: Thrombocythemia 1; OMIM: 187950; MONDO:0008554 Thrombocytopenia, congenital amegakaryocytic; OMIM: 604498; MONDO: 0011469, Thrombocytopenia 9; OMIM: 620478; MONDO:0957572 Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (loss of function vs gain of function), inheritance pattern (autosomal dominant vs autosomal recessive) and phenotypic variability (thrombocythemia vs thrombocytopenia) between these two phenotypes thus the disorders have been split. Conversly, Thrombocytopenia, congenital amegakaryocytic and Thrombocytopenia 9 were considered a single disease entity with semidominant inheritance resulting in milder thrombocytopenia in monoallelic individuals and more severe disease in biallelic cases. *THPO* was first reported in relation to congenital amegakaryocytic thrombocytopenia inherited in a semidominant manner in 2013 (Dasouki et al., PMID: 24085763) in a Micronesian family. Nonsense, missense and frameshift variants have been reported in humans thus far. The disease mechanism is loss of function. Evidence supporting this gene-disease relationship includes genetic evidence (case-level data) and experimental evidence (biochemical functions, protein interaction and animal model). Summary of Case Level Data: 12 points: Variants in this gene have been reported in at least 12 probands in 7 publications (PMIDs: 29191945, 24085763, 28559357, 36226497, 28466964, 32150607, 36534659) Summary of Experimental Data: 5.5 points: This gene-disease relationship is supported by in vitro functional assays. *THPO* is involved in megakaryopoiesis and thrombopoiesis, and loss of function variants in *THPO* lead to decrease in platelet counts (PMID: 23594368). Chen et al. showed that *THPO* physically interacts with MPL. (PMID: 20529857). A knock-out mouse model was generated by Sauvage et al, wherein homozygous KO mice recapitulated the thrombocytopenia phenotype while the heterozygous mice showed a significant reduction in platelet counts (PMID: 8627177). Additionally, CRISPR/Cas9 generated loss of function thpo-szy6 zebrafish had significant reduction of thpo expression and developed thrombocytopenia, as in humans (PMID: 35622056). In summary, there is Definitive evidence to support the gene-disease relationship of *THPO* and autosomal recessive congenital amegakaryocytic thrombocytopenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally approved by the Hemostatis and Thrombosis GCEP on March 29, 2022. It was re-evaluated on May 01, 2024. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of two probands (PMIDs: 36226497, 36534659) and a new zebrafish model (PMID: 35622056). Of note, the previous instance scored only the autosomal recessive cases but the evidence for a semidominant inheritance was considered sufficeint to update on re-evaluation.
Inheritance Pattern: AD
Disease ID:MONDO:0957572
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008554
Submitter: ClinGen
The *THPO* gene encodes the ligand for MPL, thrombopoietin, a hematopoietic growth factor that regulates the development of megakaryocytes and platelets as well as the self-renewal of hematopoietic stem cells. LUMPING AND SPLITTING CONSIDERATIONS: Thrombocythemia 1; OMIM: 187950; MONDO:0008554 Thrombocytopenia, congenital amegakaryocytic; OMIM: 604498; MONDO: 0011469 Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (loss of function vs gain of function), inheritance pattern (autosomal dominant vs autosomal recessive) and phenotypic variability (thrombocythemia vs thrombocytopenia) between these two phenotypes thus the disorders have been split. *THPO* was first reported in relation to Thrombocythemia 1 inherited in an autosomal-dominant manner in 1998 (Weistner et al., PMID: 9425899; Kondo et al, PMID: 9694695) in Dutch and Japanese families, respectively. Variants in the 5'UTR and the intron 2 splice donor site have been reported in humans. The disease mechanism is gain of function. Evidence supporting this gene-disease relationship includes genetic evidence (case-level and family data) and experimental evidence (biochemical functions and protein interaction). Summary of Case Level Data: 10.35 points: Variants in this gene have been reported in at least 13 probands in 12 publications (PMIDs: 9694695, 9425899, 10583217, 18367486, 22194398, 32430933, 19553636, 22453305, 32067437, 37962621, 38548144, 36811253). Variants in this gene segregated with disease in 39 additional family members. Summary of Experimental Data: 1.5 points: This gene-disease relationship is supported by in vitro functional assays. *THPO* is directly involved in megakaryopoiesis and thrombopoiesis, and gain of function variants in *THPO* lead to increase in platelet counts (PMID: 23594368). Chen et al. showed that THPO physically interacts with MPL. (PMID: 20529857). In summary, there is Definitive evidence to support the gene-disease relationship of *THPO* and autosomal dominant thrombocythemia 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally approved by the Hemostatis and Thrombosis GCEP on March 23, 2022. It was re-evaluated on May 01, 2024. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition three new probands (PMIDs: 37962621, 38548144, 36811253).
Inheritance Pattern: AR
Disease ID:MONDO:0011469
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018000
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008554
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019111
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Oncologic
Intervention: Hematologic; Oncologic
Rationale: Individuals with Thrombocythemia may have hemorrhagic or thrombotic tendencies, and preventive measures and prompt treatment may be beneficial; Surveillance for and early treatment of oncologic complications may also be beneficial; Individuals with Amegakaryocytic thrombocytopenia may have severe and recurrent infections, and awareness may allow early and aggressive treatment of infections; Medical management (with THPO receptor agonists) has been described as beneficial, though bone marrow transplant may not be effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to THPO variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000460.4. 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 | 2 | 46 | 1 | 49 | ||
| missense | 2 | 2 | 99 | 8 | 111 | |
| nonsense | 1 | 1 | 1 | 3 | ||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | 8 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 1 | 4 | ||
| Total | 5 | 8 | 107 | 54 | 1 | 175 |
Highest pathogenic variant AF is 0.000008208686
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000451.1 | 5 | MANE Select | |
| Ensembl | ENSP00000494504.1 | 5 | MANE Select | |
| RefSeq | NP_001171068.1 | 5 | Standard | |
| RefSeq | NP_001171069.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Hematopoietic cell lineage - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- JAK-STAT-Core
- JAK STAT MolecularVariation 1
Biological Process
- positive regulation of protein phosphorylation
- multicellular organism development
- cell population proliferation
- positive regulation of cell population proliferation
- regulation of signaling receptor activity
Molecular Function
- signaling receptor binding
- cytokine activity
- hormone activity
- growth factor activity
Cellular Component
- extracellular region
- extracellular space
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000204615
- Coding exons
- 5
- Length
- 6210
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125748
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.411 | 171 | 187 | 0.915 | 0.0000106 | 2199 |
| Missense (PolyPhen) | 39 | 59.373 | 0.65687 | 714 | ||
| Synonymous | -2.11 | 105 | 80.8 | 1.30 | 0.00000451 | 851 |
| Loss of Function | 2.25 | 3 | 11.1 | 0.271 | 6.66e-7 | 111 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000070 | 0.000062 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.;
- Disease
- DISEASE: Thrombocythemia 1 (THCYT1) [MIM:187950]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.437
Intolerance Scores
- LoFtool
- 0.748
- RVIS EVS
- -0.29
- RVIS percentile EVS
- 32.94
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.354
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |