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RET
ret proto-oncogene
The RET gene provides instructions for a receptor tyrosine kinase protein involved in cell signalling, crucial for the development of various nerve cells, kidneys, and spermatogenesis. The RET proto-oncogene is vital for cellular communication, particularly in guiding the proper formation of enteric neurons, the autonomic nervous system, kidneys, and sperm production.
RET is located on the long (q) arm of chromosome 10, at band 10q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
The RET gene, also known as the ret proto-oncogene, plays a fundamental role in cell signalling pathways. It provides instructions for creating a protein that acts as a receptor on the surface of cells, facilitating communication between the cell's external environment and its interior. This protein is particularly important for the normal development and function of several cell types, including various nerve cells within the intestine (enteric neurons) and the autonomic nervous system, which controls involuntary bodily functions like heart rate. Beyond neural development, the RET protein is also essential for the proper formation of the kidneys and for the process of sperm production (spermatogenesis).
Dysregulation of RET protein function, often due to genetic variants, can lead to a range of health conditions. These include developmental disorders such as Hirschsprung disease, characterised by severe constipation, as well as various forms of cancer, notably Multiple Endocrine Neoplasia type 2 (MEN2), which involves the development of tumours in hormone-producing glands. Given its broad developmental and cellular roles, the RET gene is a significant focus in human genetics and clinical medicine.
What the gene does
The RET gene encodes a receptor tyrosine kinase, a type of protein that spans the cell membrane. This structural arrangement allows one part of the protein to extend outside the cell, acting as a receptor, while another part remains inside, poised to transmit signals. The extracellular portion of the RET protein is designed to bind to specific signalling molecules, often referred to as growth factors, which are present in the cell's external environment. Upon binding of these growth factors, the RET protein undergoes a conformational change, leading to the activation of its intracellular tyrosine kinase domain.
The activated kinase domain then initiates a complex cascade of phosphorylation events within the cell. This involves adding phosphate groups to specific tyrosine residues on other proteins, thereby altering their activity and triggering a series of downstream chemical reactions. These reactions collectively instruct the cell to carry out specific biological processes, such as cell division, differentiation (maturing into specialised cell types), or migration. For example, in embryonic development, RET signalling is critical for the migration and survival of neural crest cells that form the enteric nervous system.
Normal RET signalling is indispensable for the proper development of numerous physiological systems. It is essential for the formation of the enteric neurons, which regulate gut motility, and for the development of the autonomic nervous system. Additionally, RET function is required for normal kidney development and contributes to the intricate process of spermatogenesis. Disruptions in this finely tuned signalling pathway, whether due to genetic variants affecting protein structure or regulation, can impair these developmental processes and cellular functions, leading to various pathologies.
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Chromosome location
The RET gene is situated on the long arm of chromosome 10, specifically at position 10q11.21. This location refers to the band q11.21 on chromosome 10. Genes located on chromosome 10 are organised within the DNA molecule, which contains the genetic instructions for various proteins essential for human development and function. The precise positioning of RET on this chromosome band helps in understanding its genetic context and how it might be inherited or involved in chromosomal rearrangements.
Protein structure
The RET protein is a transmembrane receptor tyrosine kinase comprising 1114 amino acids. It possesses a distinct modular architecture, with several key functional regions and domains.
The extracellular portion of the RET protein contains several cadherin-like regions crucial for ligand binding and receptor dimerisation. These include the Cadherin-like region 1 (CLD1), spanning amino acids 29-153, which contributes to the receptor's overall extracellular structure. A dedicated Cadherin domain is found between amino acids 168-272, central to its adhesive and signalling properties. Further cadherin-like elements are present, such as Cadherin-like region 3 (CLD3) from amino acids 265-379 and Cadherin-like region 4 (CLD4) from amino acids 405-506, all playing roles in growth factor interaction.
The intracellular segment of the RET protein contains the critical catalytic component: the Protein kinase domain, located between amino acids 724-1016. This domain is responsible for the tyrosine kinase activity that initiates intracellular signalling cascades upon receptor activation, transferring phosphate groups to target proteins within the cell.
Key variants
Genetic variants within the RET gene can encompass a broad spectrum of changes to its DNA sequence. These variants include single nucleotide changes, insertions, deletions, and larger chromosomal rearrangements. The consequence of a variant depends on its specific location within the gene and how it alters the structure or function of the encoded RET protein. Some variants may lead to a non-functional protein, while others might result in a protein with altered activity or even constitutive (always-on) activity. The clinical impact of RET variants varies significantly, ranging from benign changes with no observable effect to pathogenic alterations strongly associated with severe inherited conditions or increased cancer risk.
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.1010_1017del | p.Glu337fs | Pathogenic/Likely pathogenic | ★★☆☆ | RET-related disorder |
c.1471C>T | p.Gln491Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1495C>T | p.Gln499Ter | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 2 |
c.1597G>T | p.Gly533Cys | Pathogenic | ★★☆☆ | Familial medullary thyroid carcinoma |
c.1759+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | RET-related disorder |
c.1825T>C | p.Cys609Arg | Pathogenic | ★★☆☆ | Familial medullary thyroid carcinoma |
c.1825T>G | p.Cys609Gly | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia type 2A |
c.1826G>A | p.Cys609Tyr | Pathogenic | ★★☆☆ | MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE |
c.1826G>C | p.Cys609Ser | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1826G>T | p.Cys609Phe | Pathogenic | ★★☆☆ | not specified |
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 RET gene are linked to several inherited conditions, primarily affecting development and increasing the risk of specific tumour types. One well-known association is with Multiple Endocrine Neoplasia type 2 (MEN2), which includes subtypes like Multiple Endocrine Neoplasia type 2A and Multiple Endocrine Neoplasia type 2B. These are hereditary cancer syndromes characterised by the development of tumours in various endocrine glands. RET variants are also a common genetic cause of Hirschsprung disease, a congenital condition affecting the large intestine due to a lack of nerve cells. Additionally, Familial medullary thyroid carcinoma, a form of thyroid cancer, is another condition associated with specific RET variants.
Inheritance pattern
Conditions caused by pathogenic RET variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the RET gene is extensively evaluated within the NHS Genomic Medicine Service, reflecting its significance in genetic health. It is included in numerous NHS national genomic test directories through PanelApp, indicating its relevance across a wide range of clinical presentations. For instance, RET is part of panels for 'Additional findings health related' and 'Additional findings health related - children', suggesting its broad applicability in identifying incidental but important genetic findings. It is also assessed in the context of various cancer susceptibilities, including 'Adult solid tumours cancer susceptibility' and 'Childhood solid tumours cancer susceptibility', as well as specific endocrine neoplasias like 'Multiple endocrine neoplasia type 2' (R218) and 'Endocrine neoplasia' (R217). Furthermore, RET is included in panels for developmental conditions such as 'Hirschsprung disease' (R177) and 'Foetal anomalies' (R21), underscoring its role in both developmental disorders and inherited cancer predispositions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that general healthy lifestyle practices, such as maintaining a balanced diet, engaging in regular physical activity, and avoiding smoking, can contribute to overall well-being. These practices are broadly recommended for the general population to support health and potentially reduce the risk of many chronic diseases. While specific lifestyle interventions directly targeting the effects of RET gene variants are not established, adopting a healthy lifestyle may help individuals manage overall health and potentially mitigate some general health risks. It is important to discuss any specific lifestyle changes with a healthcare professional, especially when managing an inherited condition.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that any specific dietary supplements can prevent, treat, or directly mitigate the effects of conditions associated with RET gene variants. While some supplements are marketed for general health benefits, their efficacy in genetically determined conditions is not supported by robust clinical trials. Individuals considering taking any supplements should always consult with a healthcare provider to ensure they are safe, appropriate, and do not interfere with existing medical treatments. A healthcare professional can offer personalised advice based on individual health needs and circumstances.
Frequently asked questions
What does the RET gene do?
The RET gene provides instructions for a protein that acts as a receptor on cell surfaces. This protein is crucial for cell signalling, particularly in the development of nerve cells (like those in the intestine and autonomic nervous system), kidney formation, and sperm production.
What conditions are associated with RET gene variants?
Variants in the RET gene are associated with several conditions, including Multiple Endocrine Neoplasia type 2 (MEN2), Familial medullary thyroid carcinoma, and Hirschsprung disease.
Is RET a cancer gene?
Yes, RET is considered a proto-oncogene, meaning that certain pathogenic variants can increase the risk of developing specific types of cancer, such as medullary thyroid carcinoma and other endocrine tumours.
How is RET inherited?
RET-associated conditions, such as Multiple Endocrine Neoplasia type 2 and Familial medullary thyroid carcinoma, typically follow an autosomal dominant inheritance pattern. This means only one copy of an altered gene in each cell is sufficient to cause the condition.
What is Hirschsprung disease?
Hirschsprung disease is a congenital condition where nerve cells are missing in parts of the large intestine, leading to severe constipation or blockage. Pathogenic variants in the RET gene are a common genetic cause of this disorder.
Are there lifestyle changes or supplements that can prevent RET-associated conditions?
There is no conclusive evidence that specific lifestyle changes or dietary supplements can prevent or cure conditions associated with RET gene variants. General healthy living practices are beneficial for overall health, and any specific health concerns or interventions should be discussed with a healthcare professional.
References
- Chatterjee S, Kapoor A, Akiyama JA. Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease. Cell. 2016. PMID: 27693352
- Tomuschat C, Puri P. RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis. Pediatric surgery international. 2015. PMID: 26164711
- Burnichon N, Vescovo L, Amar L. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Human molecular genetics. 2011. PMID: 21784903
- Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nature reviews. Cancer. 2005. PMID: 15864278
- Koch CA. Molecular pathogenesis of MEN2-associated tumors. Familial cancer. 2005. PMID: 15883703
- Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine & growth factor reviews. 2005. PMID: 15982921
- Kouvaraki MA, Shapiro SE, Perrier ND. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid : official journal of the American Thyroid Association. 2005. PMID: 16029119
- Panta GR, Du L, Nwariaku FE. Direct phosphorylation of proliferative and survival pathway proteins by RET. Surgery. 2005. PMID: 16153436
- Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer letters. 2004. PMID: 15013219
- Pützer BM, Drosten M. The RET proto-oncogene: a potential target for molecular cancer therapy. Trends in molecular medicine. 2004. PMID: 15242684
- Santoro M, Carlomagno F, Melillo RM. Dysfunction of the RET receptor in human cancer. Cellular and molecular life sciences : CMLS. 2004. PMID: 15583857
- Alberti L, Carniti C, Miranda C. RET and NTRK1 proto-oncogenes in human diseases. Journal of cellular physiology. 2003. PMID: 12652644
- Neumann HP, Bausch B, McWhinney SR. Germ-line mutations in nonsyndromic pheochromocytoma. The New England journal of medicine. 2002. PMID: 12000816
- Baynash AG, Hosoda K, Giaid A. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell. 1994. PMID: 8001160
- Adam MP, Bick S, Mirzaa GM. Multiple Endocrine Neoplasia Type 2. 1993. PMID: 20301434