MEN1
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Menin is a
In vitro studies have shown that menin is localized to the nucleus, possesses two functional
History
In 1988, researchers at Uppsala University Hospital and the Karolinska Institute in Stockholm mapped the MEN1 gene to the long arm of chromosome 11.[7] The gene was finally cloned in 1997.[8]
Genomics
The gene is located on long arm of chromosome 11 (11q13) between base pairs 64,570,985 and 64,578,765. It has 10 exons and encodes a 610-amino acid protein.
Over 1300 mutations have been reported to date (2010). The majority (>70%) of these are predicted to lead to truncated forms are scattered throughout the gene. Four - c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur in 4.5%, 2.7%, 2.6% and 2.5% of families.[6]
Clinical implications
The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas (the 3 "P"s). While these neoplasias are often benign (in contrast to tumours occurring in
MEN1 pituitary tumours are adenomas of anterior cells, typically prolactinomas or growth hormone-secreting. Pancreatic tumours involve the islet cells, giving rise to gastrinomas or insulinomas. In rare cases, adrenal cortex tumours are also seen.
Role in cancer
Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin resulting in the inability of MEN1 to act as a tumor suppressor gene.[9] Such mutations in MEN1 have been associated with defective binding of encoded menin to proteins implicated in genetic and epigenetic mechanisms.[10] Menin is a 621 amino acid protein associated with insulinomas[11] which acts as an adapter while also interacting with partner proteins involved in vital cell activities such as transcriptional regulation, cell division, cell proliferation, and genome stability. Insulinomas are neuroendocrine tumors of the pancreas with an incidence of 0.4 %[citation needed] which usually are benign solitary tumors but 5-12 % of cases have distant metastasis at diagnosis.[12] These familial MEN-1 and sporadic tumors may arise either due to loss of heterozygosity or the chromosome region 11q13 where MEN1 is located, or due to presence of mutations in the gene.[13][14]
MEN1 mutations comprise mostly frameshift deletions or insertions, followed by nonsense, missense,
Although the exact function of MEN1 is not known, the
In a study of 12 sporadic carcinoid tumors of the lung, five cases involved inactivation of both copies of the MEN1 gene. Of the five carcinoids, three were atypical and two were typical. The two typical carcinoids were characterized by a rapid proliferative rate with a higher mitotic index and stronger Ki67 positivity than the other typical carcinoids in the study. Consequently, the carcinoid tumors with MEN1 gene inactivation in the study were considered to be characterized by more aggressive molecular and histopathological features than those without MEN1 gene alterations.[23]
Interactions
MEN1 has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000133895 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024947 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: MEN1 multiple endocrine neoplasia I".
- ^ PMID 20833329.
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- S2CID 20132064.
- ^ Metz DC, Jensen RT, Bale AE, Skarulis MC, Eastman RC, Nieman L, Norton JA, Friedman E, Larsson C, Amorosi A, Brandi ML, Marx SJ (1994). "Multiple endocrine neoplasia type I. Clinical features and management". In Bilezikian JP, Levine MA, Marcus, R (eds.). The Parathyroids. New York: Raven Press Publishing Co. pp. 591–646.
- PMID 9361035.
- PMID 12874027.
- ^ S2CID 44195141.
- S2CID 18116746.
- PMID 15199122.
- PMID 12509449.
- PMID 12169273.
Further reading
- Tsukada T, Yamaguchi K, Kameya T (2002). "The MEN1 gene and associated diseases: an update". Endocrine Pathology. 12 (3): 259–73. S2CID 30681290.
- Kong C, Ellard S, Johnston C, Farid NR (November 2001). "Multiple endocrine neoplasia type 1Burin from Mauritius: a novel MEN1 mutation". S2CID 71097157.
- Thakker RV (2002). "Multiple endocrine neoplasia". Hormone Research. 56 (Suppl 1): 67–72. S2CID 85195319.
- Stowasser M, Gunasekera TG, Gordon RD (December 2001). "Familial varieties of primary aldosteronism". Clinical and Experimental Pharmacology & Physiology. 28 (12): 1087–90. S2CID 23091842.
- Kameya T, Tsukada T, Yamaguchi K (2004). "Recent Advances in MEN 1 Gene Study for Pituitary Tumor Pathogenesis". Recent advances in MEN1 gene study for pituitary tumor pathogenesis. Frontiers of Hormone Research. Vol. 32. pp. 265–91. PMID 15281352.
- Balogh K, Rácz K, Patócs A, Hunyady L (November 2006). "Menin and its interacting proteins: elucidation of menin function". Trends in Endocrinology and Metabolism. 17 (9): 357–64. S2CID 8063335.
- Lytras A, Tolis G (2006). "Growth hormone-secreting tumors: genetic aspects and data from animal models". Neuroendocrinology. 83 (3–4): 166–78. S2CID 45606794.
External links
- GeneReviews/NIH/NCBI/UW entry on Multiple Endocrine Neoplasia Type 1
- MEN1 gene variant database Archived 2017-10-10 at the Wayback Machine
- MEN1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: O00255 (Menin) at the PDBe-KB.