| Written | 1999-05 | Alain Calender |
| Service de genetique moleculaire et medicale, hopital Edouard-Herriot, batiment B7, 5, place d'Arsonval, 69437 Lyon 03, France |
| Identity |
| HGNC (Hugo) | MEN1 |
| LocusID (NCBI) | 4221 |
| Atlas_Id | 148 |
| Location | 11q13.1 [Link to chromosome band 11q13] |
| Location_base_pair | Starts at 64570986 and ends at 64578188 bp from pter ( according to hg19-Feb_2009) [Mapping MEN1.png] |
| Fusion genes (updated 2016) | MEN1 (11q13.1) / ATP5G2 (12q13.13) | MEN1 (11q13.1) / RNF44 (5q35.2) | NBEAL1 (2q33.2) / MEN1 (11q13.1) |
| Note | Mutiple Endocrine neoplasia type 1: MEN1 (or Wermer syndrome) is an inherited predisposition to parathyroid, endocrine pancreas, pituitary, adrenal and neuroendocrine tumors and segregates as an autosomal dominant disease with high penetrance |
| DNA/RNA |
 | |
| structure of the MEN1 gene (The European Consortium on MEN1, 1997) | |
| Description | the MEN1 gene spans 9 Kb of the genome and is characterized by 10 exons; exon 1 and the 3' 832 bp of exon 10 are untranslated. The figure shows the general structure of the gene and some of germline mutations in patients affected by inherited MEN1 disease |
| Transcription | a major 2,8 Kb transcript is detected in all tissues tested; a large 4,0 Kb mRNA has been characterized in the pancreas and in the thymus but the 5' structure of the MEN1 gene and the promoter region remain to date unknown; the 2,8 Kb major mRNA could be initiated inside exon 1 |
| Protein |
| Description | the MEN1 protein, menin, contains 610 amino-acids (67 Kda); contains two nuclear localization signals (NLS-1 and NLS-2) at the C-terminal end of the protein (exon 10), between amino-acids 479-497 for NLS-1 and 588-608 for NLS-2; this has been shown in vitro by deletion mutants construction with GFP-coexpressing vectors |
| Expression | menin is widely expressed and mainly in testis and central nervous system; murine equivalent to MEN1 has been cloned and most of the expression data have been confirmed in murine tissues, either in adults and during embryogenesis by RNA in situ experiments |
| Localisation | primarily localized in the nucleus and could translate in the cytoplasm during specific steps of the cell cycle |
| Function | the MEN1 gene is a growth-suppressor gene, as shown by allelic deletion (LOH) in tumoral DNA from MEN1 patients; menin has been showed to interact with the AP1 transcrition factor through his JunD component; this interaction involves mainly the first 40 amino-acids at the N-terminal end of menin and some specifics amino-acids in the central domain of the protein; Menin interacts specifically with JunD but with none of the other AP1 proteins, such as JunB, c-Jun, c-Fos and Fra1/2; among 11 missense mutations described in MEN1 patients, the authors reported that four of them decreased or abolished binding to JunD suggesting a separate domain between amino-acids residues 139 and 142 could have a critical role in menin-JunD interaction; using mammalian two-hybrid assays, menin has been shown to repress JunD-mediated transcriptionnal activation but most of menin mutatnts with impaired JunD-binding properties lossed this inhibitory activity; strikingly, overexpression of normal or mutant menin in similar experimental assays led to the absence of repressional activity suggesting that unknown factors could be involved in the menin-JunD interaction; new partners binding menin will be probably characterized in a near future and help us to understand the MEN1-related pathways |
| Homology | no homology has been found to date either by comparison of primary sequence and secondary/tertiary structure of this protein with all known proteins involved in cellular physiology |
| Mutations |
| Germinal | germline mutations in the MEN1 gene cause familial and sporadic multiple endocrine neoplasia type 1 (MEN1) and the majority of mutations described predict premature protein truncation either by nonsenses and frameshifts in coding sequences; missense mutations have been identified in ˜ 30% of cases and when characterized in sporadic cases, most of them need analysis of a large (> 50) number of control individuals in order to exclude frequent polymorphisms; interestingly, all truncating mutations affect one or both NLS's and no missense mutations were observed inside NLS-1 and NLS-2; mutations are spread over the gene and most of them occur once in a single family; some mutations were observed in more than one family and when a common ancestor was excluded by haplotyping, these recurrent mutations might be accounted for 'hot-spots' in the MEN1 sequence; most recurrent mutations are nonsenses and frameshifts in exons 2 and 10; for example, single base deletion occurs frequently at nucleotide 1650 in exon 10 and has been related to the presence of an highly repetitive motif (CCCCCCCG) in this region inducing replication errors by slipped-strand mispairing; between 10 and 15% of sporadic MEN1 could be explained by de novo mutations, but this must be confirmed by an exhautive analysis of affected individuals and both parents |
| Implicated in |
| Note | |
| Entity | Multiple Endocrine Neoplasia type 1 or Wermer Syndrome |
| Disease | an inherited autosomal dominant predisposition to endocrine tumors, including parathyroids, endocrine pancreas, pituitary, adrenal glands, and the diffuse neuroendocrine tissues deriving from foregut; non-endocrine tumors have been observed in some MEN1 patients, including ependymoma, meningioma, cutaneous angiofibroma and lipoma, melanoma and rare visceral lesions such as rhabdomyosarcoma and leiomyoma; MEN1 is highly penetrant and more than 90% of gene-carriers will present biological and/or clinical signs of the disease affter the fifth decade; around 5-10% of patients have an agressive disease before age 20 |
| Prognosis | it is mainly related to metabolic and organic complications of hormonal hypersecretion by tumoral cells (Zollinger-Ellison syndrome induced by gastrinoma, hyperinsulinism, hyperparathyroidism, hyeperaldoseronism, Cushing syndrome, hyperprolactinemia, acromegaly; more than 30-50% of digestive neuroendocrine tumors and those localized in thymus and bronchi have a metastatic potential |
| Bibliography |
| Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. |
| Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL |
| Cell. 1999 ; 96 (1) : 143-152. |
| PMID 9989505 |
| Characterization of mutations in patients with multiple endocrine neoplasia type 1. |
| Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV |
| American journal of human genetics. 1998 ; 62 (2) : 232-244. |
| PMID 9463336 |
| Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. |
| Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjöld M |
| Proceedings of the National Academy of Sciences of the United States of America. 1990 ; 87 (5) : 1968-1972. |
| PMID 1968641 |
| Genetic testing in multiple endocrine neoplasia and related syndromes. |
| Calender A |
| Forum (Genoa, Italy). 1998 ; 8 (2) : 146-159. |
| PMID 9666051 |
| [Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)] |
| Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M |
| Annales d'endocrinologie. 1998 ; 59 (6) : 444-451. |
| PMID 10189986 |
| Positional cloning of the gene for multiple endocrine neoplasia-type 1. |
| Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ |
| Science (New York, N.Y.). 1997 ; 276 (5311) : 404-407. |
| PMID 9103196 |
| Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism. |
| Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, Ito K, Shingu K, Kobayashi S, Amano J, Fukushima Y |
| American journal of medical genetics. 1998 ; 80 (3) : 221-222. |
| PMID 9843042 |
| Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. |
| Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A |
| American journal of human genetics. 1998 ; 63 (2) : 455-467. |
| PMID 9683585 |
| Menin, the product of the MEN1 gene, is a nuclear protein. |
| Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC |
| Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (4) : 1630-1634. |
| PMID 9465067 |
| Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin. |
| Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC, Pham TA, Lubensky IA |
| Laboratory investigation; a journal of technical methods and pathology. 1999 ; 79 (3) : 301-310. |
| PMID 10092066 |
| A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1. |
| Kishi M, Tsukada T, Shimizu S, Futami H, Ito Y, Kanbe M, Obara T, Yamaguchi K |
| Japanese journal of cancer research : Gann. 1998 ; 89 (1) : 1-5. |
| PMID 9510467 |
| Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. |
| Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjö M |
| Nature. 1988 ; 332 (6159) : 85-87. |
| PMID 2894610 |
| Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. |
| Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Wit MJ, Lips CJ, Höppener JW, Khodaei S, Grant AL, Weber G, Kytölä S, Teh BT, Farnebo F, Thakker RV |
| Human molecular genetics. 1997 ; 6 (7) : 1177-1183. |
| PMID 9215690 |
| Menin mutations in patients with multiple endocrine neoplasia type 1. |
| Mayr B, Apenberg S, Rothämel T, von zur Mühlen A, Brabant G |
| European journal of endocrinology / European Federation of Endocrine Societies. 1997 ; 137 (6) : 684-687. |
| PMID 9437237 |
| Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. |
| Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A |
| Human mutation. 1999 ; 13 (1) : 54-60. |
| PMID 9888389 |
| Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1. |
| Shimizu S, Tsukada T, Futami H, Ui K, Kameya T, Kawanaka M, Uchiyama S, Aoki A, Yasuda H, Kawano S, Ito Y, Kanbe M, Obara T, Yamaguchi K |
| Japanese journal of cancer research : Gann. 1997 ; 88 (11) : 1029-1032. |
| PMID 9439676 |
| Characterization of the mouse Men1 gene and its expression during development. |
| Stewart C, Parente F, Piehl F, Farnebo F, Quincey D, Silins G, Bergman L, Carle GF, Lemmens I, Grimmond S, Xian CZ, Khodei S, Teh BT, Lagercrantz J, Siggers P, Calender A, Van de Vem V, Kas K, Weber G, Hayward N, Gaudray P, Larsson C |
| Oncogene. 1998 ; 17 (19) : 2485-2493. |
| PMID 9824159 |
| A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. |
| Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, Nordenskjöld M, Pearce CJ, Carmichael D, Larsson C, Harris PE |
| American journal of human genetics. 1998 ; 63 (5) : 1544-1549. |
| PMID 9792884 |
| Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. |
| Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Salmela P |
| The Journal of clinical endocrinology and metabolism. 1998 ; 83 (8) : 2621-2626. |
| PMID 9709921 |
| Genetic aspects of adenomatosis of endocrine glands. |
| WERMER P |
| The American journal of medicine. 1954 ; 16 (3) : 363-371. |
| PMID 13138607 |
| Citation |
| This paper should be referenced as such : |
| Calender, A |
| MEN1 (multiple endocrine neoplasia I) |
| Atlas Genet Cytogenet Oncol Haematol. 1999;3(2):75-77. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/MEN1ID148.html |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ] |
|
del(11)(q23q23) KMT2A/CBL;t(11;11)(q23;q23) KMT2A/CBL
del(11)(q23q23) KMT2A/ARHGEF12 t(1;11)(p32;q23) KMT2A/EPS15 t(3;11)(q21;q23) KMT2A/EEFSEC |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 6 ] |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Multiple endocrine neoplasia type 1 (MEN1) |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Sep 28 15:57:34 CEST 2016 |
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