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MEN1
menin 1
The MEN1 gene provides instructions for producing menin, a protein crucial for regulating cell proliferation and acting as a tumour suppressor, with pathogenic variants linked to multiple endocrine neoplasia type 1. MEN1 is a gene that codes for the menin protein, which functions as a tumour suppressor, helping to control cell growth and division.
MEN1 is located on the long (q) arm of chromosome 11, at band 11q13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The MEN1 gene, also known as menin 1, plays a fundamental role in maintaining normal cellular processes, particularly those governing cell division and growth. It encodes a protein called menin, which functions to restrict excessive cellular division, a characteristic feature of proteins that guard against tumour development [PMID:10205261].
Menin is found within the nucleus of various cell types throughout the body, suggesting its involvement in a wide array of cellular functions. Its multifaceted roles include potential contributions to DNA replication and repair mechanisms, as well as influencing cellular pathways that determine when damaged cells undergo self-destruction. Dysregulation of these processes due to pathogenic MEN1 variants can lead to the development of specific endocrine tumours, most notably those seen in Multiple Endocrine Neoplasia type 1 [PMID:11381269].
What the gene does
The primary function of the MEN1 gene is to produce menin, a protein that operates as a key tumour suppressor. Within the cell nucleus, menin exerts its tumour suppressive effects by modulating crucial cellular pathways involved in growth, division, and DNA integrity [PMID:15340061]. A significant aspect of menin's function involves its interaction with numerous other proteins, including several transcription factors. These regulatory molecules attach to distinct genomic regions, switching gene expression up or down as needed. Various downstream targets of these transcription complexes influence how rapidly cells divide.
Menin's regulatory roles extend to several fundamental cellular processes. It is hypothesised to participate in DNA copying (replication) and the intricate repair mechanisms that correct DNA damage, both of which are critical for preventing genetic mutations that can lead to cancer. Furthermore, menin may influence apoptosis, the cell's controlled self-destruction mechanism, which removes damaged or unwanted cells, thus preventing their unchecked growth. By integrating these diverse functions, menin contributes to maintaining genomic stability and preventing the aberrant cell growth characteristic of tumour development. Disruptions to menin's normal function due to pathogenic gene variants can therefore compromise these protective mechanisms, leading to the development of various endocrine tumours.
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Chromosome location
The MEN1 gene is located on the long (q) arm of chromosome 11, specifically at position 13.1, which is denoted as 11q13.1. This precise location on the human genome ensures its appropriate expression and function. The gene spans a region of DNA that provides the genetic blueprint for producing the menin protein, which consists of 610 amino acids.
Protein structure
The MEN1 gene codes for the menin protein, which comprises 610 amino acids. While the overall structure of menin facilitates its diverse interactions and functions, specific regions have been identified that are crucial for its activity [PMID:12424232]. One such region, located between amino acids 214 and 390, is involved in the interaction with FANCD2 (Fanconi Anaemia Complementation Group D2). This interaction highlights menin's potential role in DNA repair pathways. Additionally, a distinct Disordered region within the protein, spanning amino acids 460 to 552, suggests a flexible segment that may undergo conformational changes to interact with multiple binding partners or to facilitate dynamic cellular processes.
Key variants
Variants within the MEN1 gene refer to alterations in its DNA sequence. These changes can range from single nucleotide substitutions to larger deletions or insertions. Numerous variants (hundreds) in the MEN1 gene have been documented in medical literature. Some variants may have no impact on protein function, while others, termed pathogenic variants, can disrupt the normal production or function of the menin protein. These pathogenic variants are typically associated with an increased risk of developing specific endocrine tumours. The clinical significance of a MEN1 variant is determined through careful genetic analysis and correlation with established medical literature.
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.1001_1005dup | p.Glu336fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1006dup | p.Glu336fs | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1010C>A | p.Ala337Asp | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1013del | p.Leu338fs | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1013dup | p.Gln339fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1015C>T | p.Gln339Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1022G>A | p.Trp341Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1045C>T | p.Gln349Ter | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1049+1G>A | - | Pathogenic | ★★☆☆ | Multiple endocrine neoplasia, type 1 |
c.1049+1G>C | - | 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 MEN1 gene are primarily associated with an inherited disorder known as Multiple Endocrine Neoplasia type 1. This condition is characterised by the development of tumours, which can be benign or malignant, in two or more of the body's hormone-producing endocrine glands. The parathyroid glands, pituitary gland, and pancreas are most commonly affected in individuals with Multiple Endocrine Neoplasia type 1. MEN1 variants have also been identified in some patients with familial isolated hyperparathyroidism, a condition involving overactive parathyroid glands. In addition, acquired (somatic) MEN1 variants have been found in certain sporadic (non-hereditary) tumours, such as parathyroid adenomas and specific pancreatic tumours.
Inheritance pattern
Conditions caused by pathogenic MEN1 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 MEN1 gene is recognised within several NHS Genomic Medicine Service pathways, as indicated by its inclusion on various PanelApp panels. This demonstrates its clinical significance for diagnosis and management within the National Health Service. MEN1 is listed with a 'green' rating across multiple panels, signifying strong evidence for its gene-disease association. These panels include 'Additional findings health related' (for both adults and children), 'Adult solid tumours cancer susceptibility', 'Childhood solid tumours cancer susceptibility', 'Endocrine neoplasia', 'Familial hyperparathyroidism or Hypocalciuric hypercalcaemia', and several panels related to inherited phaeochromocytoma and paraganglioma, as well as neuroendocrine cancers.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
While specific lifestyle interventions cannot prevent the genetic predisposition associated with MEN1 gene variants, general health recommendations may support overall well-being in individuals with or at risk of conditions linked to MEN1. Maintaining a balanced diet rich in fruits, vegetables, and whole grains is generally advised for overall health. Regular physical activity, in line with national guidelines, contributes to maintaining a healthy weight and cardiovascular fitness. Avoiding smoking and limiting alcohol intake are also standard recommendations for reducing general cancer risk. For individuals with MEN1-related conditions, it is important to adhere to medical surveillance programmes and discuss any lifestyle changes with their healthcare provider, as specific dietary or activity recommendations may be tailored to their individual clinical picture, particularly concerning conditions like hyperparathyroidism or pancreatic tumours.
Supplement considerations
There is no conclusive evidence that specific dietary supplements can prevent the development or progression of conditions associated with MEN1 gene variants. Any decision to take supplements should be made in consultation with a healthcare professional, especially given the potential for interactions with medications or existing medical conditions. For example, individuals with hyperparathyroidism, which can be associated with MEN1, need careful management of calcium and vitamin D levels. Unsupervised supplementation with calcium or vitamin D could potentially exacerbate imbalances in these minerals. Therefore, it is crucial to discuss any supplement use with a doctor or a registered dietitian to ensure it is safe and appropriate for individual health needs.
Frequently asked questions
What is the main function of the MEN1 gene?
The MEN1 gene provides instructions for making the menin protein, which acts as a tumour suppressor. Its primary function is to help regulate cell growth and division, preventing cells from multiplying uncontrollably.
What health conditions are associated with variants in the MEN1 gene?
Pathogenic variants in the MEN1 gene are predominantly associated with Multiple Endocrine Neoplasia type 1 (MEN1). This condition involves the development of tumours in various endocrine glands, most commonly the parathyroid, pituitary, and pancreas.
How is Multiple Endocrine Neoplasia type 1 (MEN1) inherited?
Multiple Endocrine Neoplasia type 1 is inherited in an autosomal dominant pattern. This means that only one copy of the altered MEN1 gene in each cell is sufficient to cause the condition.
Is the MEN1 gene involved in DNA repair?
Yes, research suggests that the menin protein, encoded by the MEN1 gene, may play a role in DNA repair processes and maintaining genomic stability within cells.
What is a tumour suppressor gene?
A tumour suppressor gene, like MEN1, encodes proteins that help control cell growth and division. These proteins typically prevent the formation of tumours by inducing cell cycle arrest, promoting DNA repair, or initiating programmed cell death (apoptosis) when cells are abnormal.
Can lifestyle changes prevent MEN1-related conditions?
While lifestyle changes cannot alter the genetic predisposition caused by MEN1 variants, maintaining a healthy lifestyle through diet, exercise, and avoiding smoking can support general well-being. Individuals with MEN1-related conditions should follow medical advice and surveillance programmes.
References
- Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends in biochemical sciences. 2013. PMID: 23850066
- Tsukada T, Nagamura Y, Ohkura N. MEN1 gene and its mutations: basic and clinical implications. Cancer science. 2009. PMID: 19068082
- Davenport C, Agha A. The role of menin in parathyroid tumorigenesis. Advances in experimental medicine and biology. 2009. PMID: 20175455
- Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Human mutation. 2008. PMID: 17879353
- Hannan FM, Nesbit MA, Christie PT. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nature clinical practice. Endocrinology & metabolism. 2008. PMID: 18084346
- La P, Desmond A, Hou Z. Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. Oncogene. 2006. PMID: 16449969
- Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nature reviews. Cancer. 2005. PMID: 15864278
- Agarwal SK, Kennedy PA, Scacheri PC. Menin molecular interactions: insights into normal functions and tumorigenesis. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2005. PMID: 16001329
- Agarwal SK, Lee Burns A, Sukhodolets KE. Molecular pathology of the MEN1 gene. Annals of the New York Academy of Sciences. 2004. PMID: 15153434
- Pannett AA, Kennedy AM, Turner JJ. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clinical endocrinology. 2003. PMID: 12699448