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MEN1 (multiple endocrine neoplasia I)

Written1999-05Alain Calender
Service de genetique moleculaire et medicale, hopital Edouard-Herriot, batiment B7, 5, place d'Arsonval, 69437 Lyon 03, France

(Note : for Links provided by Atlas : click)

Identity

HGNC (Hugo) MEN1
HGNC Alias namemenin
HGNC Previous namemultiple endocrine neoplasia I
LocusID (NCBI) 4221
Atlas_Id 148
Location 11q13.1  [Link to chromosome band 11q13]
Location_base_pair Starts at 64803514 and ends at 64811294 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MEN1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
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 no genotype-phenotype correlation were found to date in MEN1; nevertheless, most families with agressive NET have truncating mutations either in exons 2, 3, 9 or 10 but no studies have been able to find statistical evidence of this putative correlation; recent investigations suggested that some MEN1 families could express only primary hyperparathyroidism, so called familial primary hyperparathyroidism (FIHPT), an allelic variant of MEN1; MEN1 related FIHPT appears as a benign disease but hyperplasia and/or adenoma occur in all parathyroid glands; recent data suggest that this variant could be associated to missense mutations in exons 4 to 7 of the MEN1 sequence; nevertheless, such correlations remain uncertain an do not have clinical implications in medical practice; the identification of germline missense mutations in exons 4 to 7 must lead to an extensive biological and clinical screening of patients in order to exclude the occurrence of pancreatic and pituitary disease, as recently shown in a typical MEN1 family carrying a Leu264Pro in exon 5; approximately 10-15% of MEN1 families do not show any mutation in the known part of MEN1 sequence; clinical profile in these families do not differ from that of families with identified mutations and it is therefore possible that MEN1 mutations occur outside the coding sequence; deletion of part or full MEN1 sequence has been also suggested as a rare mechanism of germline mutation
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
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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
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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
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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
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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
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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
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PMID 9709921
 
Genetic aspects of adenomatosis of endocrine glands.
WERMER P
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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 ]


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 Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Multiple endocrine neoplasia type 1 (MEN1)


External links

Nomenclature
HGNC (Hugo)MEN1   7010
LRG (Locus Reference Genomic)LRG_509
Cards
AtlasMEN1ID148
Entrez_Gene (NCBI)MEN1    menin 1
AliasesMEAI; SCG2
GeneCards (Weizmann)MEN1
Ensembl hg19 (Hinxton)ENSG00000133895 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000133895 [Gene_View]  ENSG00000133895 [Sequence]  chr11:64803514-64811294 [Contig_View]  MEN1 [Vega]
ICGC DataPortalENSG00000133895
TCGA cBioPortalMEN1
AceView (NCBI)MEN1
Genatlas (Paris)MEN1
SOURCE (Princeton)MEN1
Genetics Home Reference (NIH)MEN1
Genomic and cartography
GoldenPath hg38 (UCSC)MEN1  -     chr11:64803514-64811294 -  11q13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MEN1  -     11q13.1   [Description]    (hg19-Feb_2009)
GoldenPathMEN1 - 11q13.1 [CytoView hg19]  MEN1 - 11q13.1 [CytoView hg38]
ImmunoBaseENSG00000133895
genome Data Viewer NCBIMEN1 [Mapview hg19]  
OMIM131100   613733   
Gene and transcription
Genbank (Entrez)AA877856 AJ297485 AJ297486 AJ297487 AJ297488
RefSeq transcript (Entrez)NM_000244 NM_001370251 NM_001370259 NM_001370260 NM_001370261 NM_001370262 NM_001370263 NM_130799 NM_130800 NM_130801 NM_130802 NM_130803 NM_130804
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MEN1
Alternative Splicing GalleryENSG00000133895
Gene ExpressionMEN1 [ NCBI-GEO ]   MEN1 [ EBI - ARRAY_EXPRESS ]   MEN1 [ SEEK ]   MEN1 [ MEM ]
Gene Expression Viewer (FireBrowse)MEN1 [ Firebrowse - Broad ]
GenevisibleExpression of MEN1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4221
GTEX Portal (Tissue expression)MEN1
Human Protein AtlasENSG00000133895-MEN1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)MEN1
Blocks (Seattle)MEN1
Human Protein Atlas [tissue]ENSG00000133895-MEN1 [tissue]
HPRD00564
IPIIPI00328838   IPI00182106   IPI00651636   IPI01018128   IPI00657785   IPI00657753   IPI00658093   IPI00658169   IPI00657966   
Protein Interaction databases
BioGRIDMEN1
STRING (EMBL)MEN1
ZODIACMEN1
Ontologies - Pathways
Litterature
PubMed319 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXMEN1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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