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MPL
MPL proto-oncogene, thrombopoietin receptor
The MPL gene provides instructions for producing the thrombopoietin receptor, a protein vital for the proliferation of specific blood cells and the maintenance of haematopoietic stem cells. The MPL gene encodes the thrombopoietin receptor (TPOR), a cell surface protein that plays a critical role in the production of megakaryocytes, which are precursors to platelets.
MPL is located on the short (p) arm of chromosome 1, at band 1p34.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MPL proto-oncogene, thrombopoietin receptor gene, often referred to simply as MPL, contains the genetic blueprint for the thrombopoietin receptor protein. This receptor is fundamental in the process of blood cell development, particularly for cells involved in blood clotting.
Changes within the MPL gene can disrupt the normal functioning of this receptor, potentially leading to disorders characterised by abnormal platelet counts or bone marrow issues.
What the gene does
The protein produced from the MPL gene, the thrombopoietin receptor, promotes the growth and division of cells. It is especially important for the proliferation of megakaryocytes, which are large bone marrow cells responsible for generating platelets-blood components essential for clotting. The receptor is activated when it binds to thrombopoietin, a hormone that regulates platelet production.
Upon activation, the thrombopoietin receptor initiates the JAK/STAT signalling pathway. This pathway transmits chemical signals from the cell's exterior to its nucleus, regulating blood cell production. Research also suggests a role for the thrombopoietin receptor in maintaining haematopoietic stem cells, which are precursor cells in the bone marrow capable of developing into all types of blood cells, including red blood cells, white blood cells, and platelets.
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Chromosome location
The MPL gene is situated on the short (p) arm of chromosome 1, specifically at position 1p34.2. This genomic location is home to the instructions required for synthesising the thrombopoietin receptor protein.
Protein structure
The MPL protein is composed of 635 amino acids. Its structural organisation includes several key regions. Among these are two Fibronectin type-III domains: Fibronectin type-III 1, spanning amino acids 172-281, and Fibronectin type-III 2, located from amino acids 392-486. A Disordered region is found between amino acids 205-232. Additionally, specific motifs are present, including the WSXWS motif at amino acids 474-478 and the Box 1 motif at amino acids 528-536.
Key variants
Variants within the MPL gene can influence the structure and function of the thrombopoietin receptor. Some of these genetic changes may lead to a reduction in protein function, while others might result in altered activity. The clinical significance of an MPL variant depends on its specific effect on the receptor's ability to signal and regulate cell proliferation.
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.1033C>T | p.Gln345Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.1145del | p.Pro382fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.11G>A | p.Trp4Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.1469-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.1545G>A | p.Trp515Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.1671dup | p.Asp558fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.209del | p.Pro70fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia 1 |
c.292C>T | p.Gln98Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.407C>T | p.Pro136Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
c.417dup | p.Lys140fs | Pathogenic | ★★☆☆ | Congenital amegakaryocytic thrombocytopenia |
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
Variations in the MPL gene are associated with inherited conditions primarily affecting blood cell production. One such condition is congenital amegakaryocytic thrombocytopenia, an autosomal recessive disorder characterised by very low numbers of megakaryocytes and platelets. These conditions can have significant impacts on an individual's haematological health.
Inheritance pattern
Conditions caused by pathogenic MPL variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The MPL gene is included in several NHS Genomic Medicine Service national test panels. It is part of panels for Bleeding and platelet disorders (R90), Cytopenia - NOT Fanconi anaemia (R91), Cytopenias and congenital anaemias, Inherited bleeding disorders, and Thrombocythaemia (R406), indicating its recognised role in these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the MPL gene?
The MPL gene provides instructions for making the thrombopoietin receptor protein, which is essential for the growth and division of cells, especially megakaryocytes that produce platelets for blood clotting.
How does the thrombopoietin receptor work?
The receptor is activated when thrombopoietin binds to it, triggering the JAK/STAT signalling pathway. This pathway sends chemical signals inside the cell, which helps to control the production of blood cells.
What condition is specifically mentioned in relation to MPL gene variants?
Variations in the MPL gene are associated with congenital amegakaryocytic thrombocytopenia, a condition involving very low numbers of megakaryocytes and platelets, which are crucial for blood clotting.
References
- Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010. PMID: 20428194
- Ding J, Komatsu H, Iida S. The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. Blood. 2009. PMID: 19483125
- Chaligné R, Tonetti C, Besancenot R. New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia. 2008. PMID: 18528423
- Germeshausen M, Ballmaier M, Welte K. MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease. Human mutation. 2006. PMID: 16470591
- Pikman Y, Lee BH, Mercher T. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS medicine. 2006. PMID: 16834459