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PTPN11
protein tyrosine phosphatase non-receptor type 11
The PTPN11 gene provides instructions for making the SHP-2 protein, which plays a crucial role in cellular growth, differentiation, migration, and programmed cell death. PTPN11 encodes the SHP-2 protein, a key component of the RAS/MAPK signalling pathway that regulates various essential cellular functions.
PTPN11 is located on the long (q) arm of chromosome 12, at band 12q24.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The PTPN11 gene is responsible for producing a protein called SHP-2, which is a protein tyrosine phosphatase. This protein acts as a critical regulator within cells, influencing processes such as cell division and growth (proliferation), the specialisation of cells (differentiation), cell movement (migration), and the controlled self-destruction of cells (apoptosis).
During foetal development, SHP-2 is particularly important for the proper formation of organs including the heart, blood cells, and bones. PTPN11 is classified as an oncogene, meaning that specific alterations within it can potentially contribute to the development of cancerous cells.
What the gene does
The SHP-2 protein, encoded by PTPN11, is a vital signalling molecule involved in numerous cellular pathways, most notably the RAS/MAPK signalling pathway. This pathway is a complex network of proteins that communicate signals from outside the cell to the nucleus, affecting fundamental cellular activities.
SHP-2's role as a protein tyrosine phosphatase means it removes phosphate groups from specific tyrosine amino acids on other proteins. This action can either activate or deactivate those proteins, thereby regulating their function and influencing downstream signalling events. Through this mechanism, SHP-2 impacts cell proliferation, cell survival, and cell fate decisions. Its balanced activity is essential for normal development and tissue maintenance.
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Chromosome location
The PTPN11 gene is situated on the long (q) arm of chromosome 12, specifically at position 24.13 (12q24.13). This genomic location places it within a region that is significant for various cellular functions.
Protein structure
The SHP-2 protein, encoded by PTPN11, is 593 amino acids in length and features several distinct functional regions. It contains two N-terminal SH2 domains, designated SH2 1 (amino acids 6-102) and SH2 2 (amino acids 112-216). These domains are crucial for binding to phosphotyrosine residues on other proteins, enabling SHP-2 to be recruited to specific signalling complexes. A central Tyrosine-protein phosphatase domain (amino acids 247-517) is responsible for the catalytic removal of phosphate groups. Additionally, the protein includes a Disordered region (amino acids 548-571) towards its C-terminus, which may contribute to its regulatory flexibility.
Key variants
Variants within the PTPN11 gene can lead to alterations in the SHP-2 protein, affecting its function. These changes can result in either a gain-of-function, where the protein becomes overactive, or a loss-of-function, where its activity is reduced. The specific impact of a variant often depends on its location within the gene and the resulting change in the protein's structure.
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.1381G>A | p.Ala461Thr | Pathogenic | ★★★☆ | not provided |
c.1391G>C | p.Gly464Ala | Pathogenic | ★★★☆ | RASopathy |
c.1403C>T | p.Thr468Met | Pathogenic | ★★★☆ | RASopathy |
c.1510A>G | p.Met504Val | Pathogenic | ★★★☆ | Noonan syndrome |
c.1517A>C | p.Gln506Pro | Pathogenic | ★★★☆ | RASopathy |
c.1529A>C | p.Gln510Pro | Pathogenic | ★★★☆ | LEOPARD syndrome 1 |
c.1530G>C | p.Gln510His | Pathogenic | ★★★☆ | RASopathy |
c.155C>T | p.Thr52Ile | Pathogenic | ★★★☆ | not provided |
c.166A>G | p.Ile56Val | Pathogenic | ★★★☆ | Noonan syndrome |
c.184T>G | p.Tyr62Asp | Pathogenic | ★★★☆ | Noonan syndrome 1 |
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
Pathogenic variants in the PTPN11 gene are associated with several inherited conditions, including Noonan syndrome. This genetic disorder affects development, leading to characteristic facial features, short stature, and heart defects. Other conditions linked to PTPN11 include Noonan syndrome with multiple lentigines and metachondromatosis, which involves benign bone tumours.
Inheritance pattern
Conditions caused by pathogenic PTPN11 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
PTPN11 is recognised by the UK's NHS Genomic Medicine Service, featuring on numerous PanelApp green panels. This indicates that there is strong evidence for a gene-disease association and that the gene is routinely tested for in clinical practice. Relevant panels include 'Adult solid tumours cancer susceptibility', 'Childhood solid tumours', 'RASopathies', and 'Monogenic short stature (R453)' among others.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the PTPN11 gene?
The PTPN11 gene provides instructions for the SHP-2 protein, which is vital for regulating various cellular functions such as growth, division, differentiation, and programmed cell death, primarily through its involvement in the RAS/MAPK signalling pathway.
Which conditions are associated with PTPN11 variants?
Variants in the PTPN11 gene are linked to several conditions, including Noonan syndrome, Noonan syndrome with multiple lentigines, and metachondromatosis. It can also increase the risk of certain types of cancer.
Is PTPN11 involved in cancer?
Yes, PTPN11 is considered an oncogene, meaning that specific alterations within it can contribute to cancer development. Somatic (non-inherited) variants in PTPN11 have been associated with an increased risk of blood cancers like juvenile myelomonocytic leukaemia.
References
- Gulec EY, Ocak Z, Candan S. Novel mutations in PTPN11 gene in two girls with Noonan syndrome phenotype. International journal of cardiology. 2015. PMID: 25804457
- Zhang J, Zhang F, Niu R. Functions of Shp2 in cancer. Journal of cellular and molecular medicine. 2015. PMID: 26088100
- Romano AA, Allanson JE, Dahlgren J. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010. PMID: 20876176
- Chan G, Kalaitzidis D, Neel BG. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer metastasis reviews. 2008. PMID: 18286234
- Mohi MG, Neel BG. The role of Shp2 (PTPN11) in cancer. Current opinion in genetics & development. 2007. PMID: 17227708
- Tartaglia M, Gelb BD. Germ-line and somatic PTPN11 mutations in human disease. European journal of medical genetics. 2005. PMID: 16053901
- Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annual review of genomics and human genetics. 2005. PMID: 16124853
- Keren B, Hadchouel A, Saba S. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. Journal of medical genetics. 2004. PMID: 15520399
- Bentires-Alj M, Paez JG, David FS. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer research. 2004. PMID: 15604238