OMIM :  131100

GENECARD : MEN1

CGAP : 24297

Biochemical type

• Menin is principally a nuclear protein. Marx SJ, Agarwal SK, Heppner C, Kim YS, Kester MB, Goldsmith PK, Skarulis MC, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree JS, Collins FS, Chandrasekharappa SC.

Cell type distribution

• Multiple endocrine neoplasia type 1 (MEN-1) is characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours Dreijerink KM, Roijers JF, van der Luijt RB, Hoppener JW, Lips CJ.

Chromosome human

• The MEN1 gene, which is located on chromosome 11q13…. Pannett AA, Thakker RV

• Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors. Hessman O, Lindberg D, Einarsson A, Lillhager P, Carling T, Grimelius L, Eriksson B, Akerstrom G, Westin G, Skogseid B.

• Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours. Nikiforova MN, Nikiforov YE, Biddinger P, Gnepp DR, Grosembacher LA, Wajchenberg BL, Fagin JA, Cohen RM.

• The MEN1 gene is on chromosome 11q13 Agarwal SK, Debelenko LV, Kester MB, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Heppner C, Crabtree JS, Lubensky IA, Zhuang Z, Kim YS, Chandrasekharappa SC, Collins FS, Liotta LA, Spiegel AM, Burns AL, Em mert-Buck MR, Marx SJ.

• The MEN1 locus has been previously localised to chromosome 11q13, 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, Hoppener JW, Khodaei S, Grant AL, Weber G , Kytola S, Teh BT, Farnebo F, Thakker RV, et al.

• Localization of the multiple endocrine neoplasia type I (MEN1) gene based on tumor loss of heterozygosity analysis. Emmert-Buck MR, Lubensky IA, Dong Q, Manickam P, Guru SC, Kester MB, Olufemi SE, Agarwal S, Burns AL, Spiegel AM, Collins FS, Marx SJ, Zhuang Z, Liotta LA, Chandrasekharappa SC, Debelenko LV.

• Molecular genetic mapping of the multiple endocrine neoplasia type 1 locus. Pang JT, Pook MA, Eubanks JH, Jones C, van Heyningen V, Evans GA, Thakker RV.

• Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Bale AE, Norton JA, Wong EL, Fryburg JS, Maton PN, Oldfield EH, Streeten E, Aurbach GD, Brandi ML, Friedman E, et al.

• Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Bystrom C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjold M.

• Genetic linkage analysis to restriction fragment length polymorphism (RFLP) markers assigned the gene to chromosome band 11q13.Larsson C, Nordenskjold M.

Cis-Acting effect

• 2-bp (TA) insertion at nucleotide position 341 (341insTA) in exon 2, which shifts the reading frame such that the mutant protein has a completely different amino acid sequence from codon 78 to the premature stop codon at 119. Hamaguchi K, Nguyen DC, Yanase T, Ikuyama S, Goto K, Takayanagi R, Nawata H, Kusuda Y, Fukagawa K, Sakata T.

Clinical

• Genetic, clinical, and biochemical analysis of unrelated Spanish families with multiple endocrine neoplasia type I. Chico A, Gallart L, Martin-Campos JM, Catasus L, Mayoral C, Mato E, Tortosa F, Berna L, Rodriguez-Espinosa J, Blanco-Vaca F, Matias-Guiu X, de Leiva A, Mauricio D.

• Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes. Stratakis CA.

• Multiple endocrine neoplasia type 1: recent developments and guidelines for DNA diagnosis and periodic clinical monitoring. Dreijerink KM, Roijers JF, van der Luijt RB, Hoppener JW, Lips CJ.

• Family investigation, DNA analysis and periodic examination improve quality of life and the life expectancy. Dreijerink KM, Roijers JF, Jansen-Schillhorn van Veen JM, Neijt JP, van Vroonhoven TJ, Lips CJ.

• The identification of MEN 1 mutation by employing DNA test, will facilitate early diagnosis and treatment. Kameyama K, Takami H.

• Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands. Hai N, Aoki N, Matsuda A, Mori T, Kosugi S

• Octreotide improves biochemical, radiologic, and symptomatic indices of gastroenteropancreatic neoplasia in patients with multiple endocrine neoplasia type 1 (MEN-1). Burgess JR, Greenaway TM, Parameswaran V, Shepherd JJ.

• This is a rare case of MEN type I because of the giant cystic insulinoma and the evidence of common LOH detected in all MEN type I tissues. Kataoka H, Otsuka F, Yamauchi T, Kishida M, Takahashi M, Tamiya T, Mimura Y, Ogura T, Makino H.

• Multiple endocrine neoplasia Type I. Diagnosis and therapy in a case  with classical family history. Lamberts R, Gregor M.

• Type 1 multiple endocrine neoplasia (MEN1): contribution of genetic analysis to the screening and follow-up of a large French kindred. Waterlot C, Porchet N, Bauters C, Decoulx M, Wemeau JL, Proye C, Degand PM, Aubert JP, Cortet C, Dewailly D.

• Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.  Mutch MG, Dilley WG, Sanjurjo F, DeBenedetti MK, Doherty GM, Wells SA Jr, Goodfellow PJ, Lairmore TC.

• Germline mutations in the MEN1 gene: basis for predictive genetic screening and clinical management of multiple endocrine neoplasia type 1 (MEN1) families. Bartsch D, Kopp I, Bergenfelz A, Rieder H, Deiss Y, Munch K, Rothmund M, Simon B.

• Genetic screening of MEN1 and clinically related cases. 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, Calender A, et al.

• Genetic testing in multiple endocrine neoplasia and related syndromes. Calender A.

• Menin mutations in the diagnosis and prediction of multiple endocrine neoplasia type 1. Karges W, Ludwig L, Kessler H, Wissmann A, Wagner PK, Boehm BO.

• 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.

• Multiple endocrine neoplasia type 1 and 2. 1997 diagnostic guidelines and molecular pathology. Komminoth P.

• Eighteen new polymorphic markers in the multiple endocrine neoplasia type 1 (MEN1) region. Manickam P, Guru SC, Debelenko LV, Agarwal SK, Olufemi SE, Weisemann JM, Boguski MS, Crabtree JS, Wang Y, Roe BA, Lubensky IA, Zhuang Z, Kester MB, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Emmert-Buck MR, Collins FS, Chandrasekharappa SC.

DNA Structure

• The MEN1 gene, which is located on chromosome 11q13 Pannett AA, Thakker RV.

• MEN 1 is on chromosome 11q13 and has 10 exons Kameyama K, Takami H.

• MEN1 gene, a locus encompassing a 9 kb of genomic sequence contains 10 exons, the first exon being untranslated. Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M.

• A novel germline mutation in exon 5 of the multiple endocrine neoplasia type 1 gene. Chico A, Gallart L, Mato E, Mayoral C, Martin-Campos JM, Catasus L, Rodriguez-Espinosa J, Matias-Guiu X, Blanco-Vaca F, de Leiva A.

• Construction of a 1.2-Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Lemmens I, Merregaert J, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Calender A, Parente F, Quincey D, Courseaux A, Carle GF, Gaudray P, De Wit MJ, Lips CJ, Hoppener JW, Khodaei S, Grant AL, Weber G, Kytola S, Thakker RV, et al.

Function

• Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Kaji H, Canaff L, Lebrun JJ, Goltzman D, Hendy GN.

• The protein encoded by the MEN1 gene has been shown to function in the regulation of JunD-activated transcription. Yoshimoto K.

• A novel splicing mutation (894-9 G --> A) of the MEN1 gene responsible for multiple endocrine neoplasia type 1. Kishi M, Tsukada T, Shimizu S, Hosono K, Ohkubo T, Kosuge T, Sugano K, Kanbe M, Obara T, Yamaguchi K.

• Menin and has been shown to contain two nuclear localization signals (NLS), suggesting a major function in the nucleus. Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M.

• Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction. Weber G, Friedman E, Grimmond S, Hayward NK, Phelan C, Skogseid B, Gobl A, Zedenius J, Sandelin K, Teh BT, et al.

Gene Frequencey (tumor)

• Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC.

• Allelic deletion of the MEN1 locus was identified in 18/49 (36.7%) tumors (13/30, 43.3% in EPT and 5/19, 26.3% in NET) and mutations of the MEN1 gene were present in 8/52 (15.3%) tumors (4/30 (13.3%) EPT and 4/22 (18.1%) NET). Gortz B, Roth J, Krahenmann A, de Krijger RR,  Muletta-Feurer S, Rutimann K, Saremaslani P, Speel EJ, Heitz PU, Komminoth P.

Homologue

• Characterization of a MEN1 ortholog from Drosophila melanogaster. Guru SC, Prasad NB, Shin EJ, Hemavathy K, Lu J, Ip YT, Agarwal SK, Marx SJ, Spiegel AM, Collins FS, Oliver B, Chandrasekharappa SC.

• Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene. 118: Guru SC, Crabtree JS, Brown KD, Dunn KJ, Manickam P, Prasad NB, Wangsa D, Burns AL, Spiegel AM, Marx SJ, Pavan WJ, Collins FS,  Chandrasekharappa SC.

• Studies of the murine homolog of the multiple endocrine neoplasia type 1 (MEN1) gene, men1. Bassett JH, Rashbass P, Harding B, Forbes SA,  Pannett AA, Thakker RV.

Oncogenic Activation

• Inactivation of the MEN1 tumour suppressor gene contributes to the development of sporadic MEN 1-type endocrine lesions  Bergman L,  Boothroyd C, Palmer J, Grimmond S, Walters M, Teh B, Shepherd J, Hartley L, Hayward N.

• Four mutations were detected in 4 MEN1 patients  Jakobovitz-Picard O, Olchovsky D, Berezin M, Ghodsizade A, Zahavi Z, Karasik A, Rechavi G, Friedman E.

Protein binding

• Menin interacts with Smad3 Kaji H, Canaff L, Lebrun JJ, Goltzman D, Hendy GN.

• The MEN1 gene encodes a putative growth-suppressor protein, menin, binding JunD, a transcriptional factor belonging to the AP-1 complex. Calender A.

Protein Structure

• The MEN1 gene consists of 10 exons and encodes a 610-amino acid protein named MENIN. Pannett AA, Thakker RV.

• Men1 is on chromosome 11q13 and has 10 exons. It encodes a 610 amino acid protein called MENIN.Kameyama K, Takami H.

• The protein encoded by men1 gene was called menin and has been shown to contain two nuclear localization signals (NLS), suggesting a major function in the nucleus. Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M.

Tumor gene type

• The multiple endocrine neoplasia type 1 gene (MEN1) is a tumor suppressor gene. Forsberg L, Zablewska B, Piehl F, Weber G, Lagercrantz S, Gaudray P, Hoog C, Larsson C.

• The observation of LOH involving 11q13 in MEN type 1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor.  Pannett AA, Thakker RV.

• Role of the MEN1 tumour suppressor gene in human ductal pancreatic cancer. Karges W, Maier S, Schmidt F, Gress TM, Boehm BO.

• MEN1 is a tumour suppressor gene, Valdes N, Perez de Nanclares G, Alvarez V, Castano L, Diaz-Cadorniga F, Aller J, Coto E.

• MEN1 is a tumor suppressor gene insofar as stepwise mutational inactivation of both copies can release a cell from normal growth suppression. Marx SJ, Agarwal SK, Heppner C, Kim YS, Kester MB, Goldsmith PK, Skarulis MC, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree JS, Collins FS, Chandrasekharappa SC.

• The high incidence of truncating mutations in tumors with LOH at 11q13 support the hypothesis that MENIN is a tumor suppressor gene.  Wang EH, Ebrahimi SA, Wu AY, Kashefi C, Passaro E Jr, Sawicki MP.

Tumor incidence

• MEN1 gene mutations were identified in 9 of 27 (33%) sporadic gastrinomas and 2 of 12 (17%) insulinomas. Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park WS, Agarwal SK, Debelenko LV, Kester M, Guru SC, Manickam P, Olufemi SE, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert-Buck MR, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Lubensky IA, et al.

Tumor type      

• Out of 21 patients with MEN 1,Nine patients had gastrinomas, 5 had nonfunctioning tumors, 4 had insulinomas, 2 had insulinomas and gastrinomas, and 1 had a VIPoma Bartsch DK, Langer P, Wild A, Schilling T, Celik I, Rothmund M, Nies C.

• Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC.

• MEN1 proved to be the gene most frequent L4 mutated in common-variety, nonhereditary parathyroid tumor, gastrinoma, insulinoma, or bronchial carcinoid. Marx SJ, Agarwal SK, Heppner C, Kim YS, Kester MB, Goldsmith PK, Skarulis MC, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree JS, Collins FS, Chandrasekharappa SC.

• The MEN1 gene seems to be involved in a 20-30% of sporadic parathyroid and pancreatic/bronchic neuroendocrine tumors, but less than 1% of pituitary sporadic tumors. Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M.

• Twelve unrelated (German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations. Bartsch D, Kopp I, Bergenfelz A, Rieder H, Munch K, Jager K, Deiss Y, Schudy A, Barth P, Arnold R, Rothmund M, Simon B.

• Somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.  Shan L, Nakamura Y, Nakamura M, Yokoi T, Tsujimoto M, Arima R, Kameya T, Kakudo K.