MEN1 (multiple endocrine neoplasia I)

1999-05-01   Alain Calender 

Service de genetique moleculaire et medicale, hopital Edouard-Herriot, batiment B7, 5, place dArsonval, 69437 Lyon 03, France

Identity

HGNC
LOCATION
11q13.1
LOCUSID
ALIAS
MEAI,SCG2
FUSION GENES

DNA/RNA

Atlas Image
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

Proteins

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 NLSs 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

Entity name
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

Pubmed IDLast YearTitleAuthors
99895051999Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.Agarwal SK et al
94633361998Characterization of mutations in patients with multiple endocrine neoplasia type 1.Bassett JH et al
19686411990Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors.Byström C et al
96660511998Genetic testing in multiple endocrine neoplasia and related syndromes.Calender A et al
101899861998[Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)].Calender A et al
91031961997Positional cloning of the gene for multiple endocrine neoplasia-type 1.Chandrasekharappa SC et al
98430421998Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.Fujimori M et al
96835851998Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.Giraud S et al
94650671998Menin, the product of the MEN1 gene, is a nuclear protein.Guru SC et al
100920661999Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin.Huang SC et al
95104671998A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1.Kishi M et al
28946101988Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.Larsson C et al
92156901997Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.Lemmens I et al
94372371997Menin mutations in patients with multiple endocrine neoplasia type 1.Mayr B et al
98883891999Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases.Poncin J et al
94396761997Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1.Shimizu S et al
98241591998Characterization of the mouse Men1 gene and its expression during development.Stewart C et al
97928841998A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors.Teh BT et al
97099211998Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.Teh BT et al
131386071954Genetic aspects of adenomatosis of endocrine glands.WERMER P et al

Other Information

Locus ID:

NCBI: 4221
MIM: 613733
HGNC: 7010
Ensembl: ENSG00000133895

Variants:

dbSNP: 4221
ClinVar: 4221
TCGA: ENSG00000133895
COSMIC: MEN1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000133895ENST00000312049O00255
ENSG00000133895ENST00000315422O00255
ENSG00000133895ENST00000337652O00255
ENSG00000133895ENST00000377313O00255
ENSG00000133895ENST00000377316E7EN32
ENSG00000133895ENST00000377321O00255
ENSG00000133895ENST00000377326O00255
ENSG00000133895ENST00000394374O00255
ENSG00000133895ENST00000394376O00255
ENSG00000133895ENST00000413626E7ENS2
ENSG00000133895ENST00000424912Q9GZQ5
ENSG00000133895ENST00000429702Q9GZQ5
ENSG00000133895ENST00000440873E7ET29
ENSG00000133895ENST00000450708E7EPR4

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate IQGAPsREACTOMER-HSA-5626467
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerREACTOMER-HSA-2173793
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcriptionREACTOMER-HSA-2173796
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
Deactivation of the beta-catenin transactivating complexREACTOMER-HSA-3769402
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA446760Multiple Endocrine Neoplasia Type 1DiseaseDataAnnotation, Literature, MultilinkAnnotationassociated23788249

References

Pubmed IDYearTitleCitations
212523152011DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.498
151991222004Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.266
149927272004Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.240
185989422008Menin critically links MLL proteins with LEDGF on cancer-associated target genes.198
162391402005The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.194
156403492005Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.157
178793532008Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.129
223272962012The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.102
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
166041562006Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis.80

Citation

Alain Calender

MEN1 (multiple endocrine neoplasia I)

Atlas Genet Cytogenet Oncol Haematol. 1999-05-01

Online version: http://atlasgeneticsoncology.org/gene/148/men1