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TMEM127
transmembrane protein 127
The TMEM127 gene provides instructions for a protein that acts as a tumour suppressor, regulating cell growth and division, and is associated with inherited forms of phaeochromocytoma and paraganglioma. The TMEM127 gene encodes the transmembrane protein 127, a vital component in cellular processes that helps control cell proliferation.
TMEM127 is located on the long (q) arm of chromosome 2, at band 2q11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The TMEM127 gene, also known by aliases such as FLJ20507 and FLJ22257, is responsible for producing the transmembrane protein 127. This protein plays a crucial role in cellular regulation, primarily functioning as a tumour suppressor. Its activity is essential for maintaining normal cell growth and division, preventing uncontrolled cellular proliferation that can lead to tumour formation.
Dysfunction of the TMEM127 protein, often due to specific genetic changes within the gene, has been associated with an increased susceptibility to certain neuroendocrine tumours. These include phaeochromocytomas, which develop in the adrenal glands, and paragangliomas, which can arise in various locations outside the adrenal glands.
What the gene does
The protein encoded by the TMEM127 gene acts as a tumour suppressor. Its primary role involves regulating cellular growth and division to prevent cells from proliferating too rapidly or in an uncontrolled manner. This regulatory function is critical for maintaining tissue homeostasis and preventing tumour development.
The TMEM127 protein influences a signalling pathway that is central to cell growth and survival. Research indicates that this pathway, which involves a protein complex known as mTORC1, is inhibited by the TMEM127 protein. By modulating mTORC1 activity, TMEM127 helps to put the brakes on cell proliferation when necessary. While the precise mechanisms by which TMEM127 achieves this inhibition are still under investigation, its overall effect is to suppress abnormal cell expansion. This control over cellular growth makes TMEM127 a key player in tumour prevention within the body.
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Chromosome location
The TMEM127 gene is situated on chromosome 2, specifically at position 2q11.2. This location refers to the long (q) arm of chromosome 2, within region 11.2. The gene spans an approximate length on the chromosome, containing the genetic instructions necessary for the synthesis of the transmembrane protein 127.
Protein structure
The TMEM127 protein is composed of 238 amino acids. Its structural organisation includes a Disordered region, which spans amino acids 1-27. Disordered regions are characterised by a lack of stable tertiary structure and often play roles in protein-protein interactions and signalling pathways, allowing for flexibility and adaptability in their functions.
Key variants
Genetic variations, or variants, in the TMEM127 gene can alter the function of the transmembrane protein 127. These alterations may disrupt its role as a tumour suppressor, potentially leading to dysregulation of cell growth and division. Pathogenic variants in TMEM127 are primarily associated with an increased risk of developing neuroendocrine tumours. The spectrum of these variants includes missense, nonsense, and frameshift mutations, all of which can impact protein structure and function to varying degrees.
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.115_116del | p.Leu39fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.117_120del | p.Ile41fs | Pathogenic | ★★☆☆ | Pheochromocytoma |
c.12del | p.Gly5fs | Pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.158G>A | p.Trp53Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.182del | p.Cys61fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.190C>T | p.Gln64Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1A>T | p.Met1Leu | Pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.202dup | p.Val68fs | Pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.218del | p.Gly73fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.224del | p.Val75fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
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 TMEM127 gene are primarily associated with an increased predisposition to certain neuroendocrine tumours. These include phaeochromocytoma, a tumour of the adrenal glands, and paraganglioma, which arises from neuroendocrine tissues outside the adrenal glands. Specifically, TMEM127 gene mutations are most commonly found in individuals with phaeochromocytoma, while they are rarely identified in other forms of paraganglioma. These conditions are classified as nonsyndromic, meaning they typically occur without other associated symptoms or conditions.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TMEM127 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The TMEM127 gene is included in several genomic testing panels within the UK National Health Service (NHS) Genomic Medicine Service. It is categorised as a 'green' gene on panels related to cancer susceptibility and rare diseases. This indicates that there is strong evidence for a gene-disease association and that testing for TMEM127 variants is routinely offered for specific clinical indications. These panels include Adult solid tumours cancer susceptibility, Inherited phaeochromocytoma and paraganglioma, and Multiple endocrine tumours.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for overall well-being, irrespective of genetic predispositions. For individuals with TMEM127 variants, research suggests that general health practices may support metabolic health, which could be relevant given the gene's role in cell growth pathways. A balanced diet rich in fruits, vegetables, and whole grains, along with regular physical activity, can contribute to maintaining a healthy weight and cardiovascular fitness. Limiting processed foods, excessive sugar, and saturated fats is also generally advisable.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with TMEM127 gene variants. Individuals considering any supplements should consult with a healthcare professional. A balanced diet typically provides essential nutrients, and the role of supplementary vitamins or minerals in altering disease risk related to TMEM127 has not been established.
Frequently asked questions
What is the primary function of the TMEM127 gene?
The TMEM127 gene provides instructions for making a protein that acts as a tumour suppressor. It helps to regulate cell growth and division, preventing uncontrolled cell proliferation by inhibiting a key signalling pathway called mTORC1.
What health conditions are associated with TMEM127 gene variants?
Variants in the TMEM127 gene are primarily associated with an increased risk of developing neuroendocrine tumours, specifically phaeochromocytoma, which affects the adrenal glands, and paraganglioma, which can occur outside the adrenal glands.
Is TMEM127 testing available on the NHS?
Yes, the TMEM127 gene is included in several NHS Genomic Medicine Service panels for cancer susceptibility and rare diseases. It is a 'green' gene, indicating strong evidence for its association with relevant conditions and the availability of testing for specific clinical indications.
How does TMEM127 relate to cell growth?
TMEM127 is involved in regulating cell growth by inhibiting the mTORC1 signalling pathway. This pathway promotes cell growth and survival, so TMEM127's inhibitory action helps to prevent cells from growing and dividing too quickly, functioning as a tumour suppressor.
What inheritance pattern is associated with TMEM127-related conditions?
Conditions associated with pathogenic variants in the TMEM127 gene typically follow an autosomal dominant inheritance pattern. This means that inheriting just one copy of the altered gene from a parent is sufficient to increase the risk of developing the associated conditions.
References
- Neumann HP, Sullivan M, Winter A. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. The Journal of clinical endocrinology and metabolism. 2011. PMID: 21613359
- Qin Y, Yao L, King EE. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature genetics. 2010. PMID: 20154675
- Opocher G, Schiavi F. Genetics of pheochromocytomas and paragangliomas. Best practice & research. Clinical endocrinology & metabolism. 2010. PMID: 21115163
- Yao L, Schiavi F, Cascon A. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010. PMID: 21156949
- Qin Y, Buddavarapu K, Dahia PL. Pheochromocytomas: from genetic diversity to new paradigms. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2009. PMID: 19391076