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MEN1

Identity

HGNC (Hugo) MEN1
Location 11q13
Location_base_pair Starts at 64327572 and ends at 64334764 bp from pter ( according to hg18-Mar_2006)  [Mapping]
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

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; MEN1­related 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
  

External links

Nomenclature
HGNC (Hugo)MEN1   7010
Entrez_Gene (NCBI)MEN1  4221  multiple endocrine neoplasia I
Cards
AtlasMEN1ID148
GeneCards (Weizmann)MEN1
Ensembl (Hinxton)ENSG00000133895 [Gene_View]  MEN1 [Vega]
AceView (NCBI)MEN1
Genatlas (Paris)MEN1
euGene (Indiana)4221
SOURCE (Stanford)NM_000244 NM_130799 NM_130800 NM_130801 NM_130802 NM_130803 NM_130804
Genomic and cartography
GoldenPath (UCSC)MEN1  -  11q13   chr11:64327572-64334764 -  11q13   [Description]    (hg18-Mar_2006)
EnsemblMEN1 - 11q13 [CytoView]
Mapping of homologs : NCBIMEN1 [Mapview]
OMIM131100   145000   
Gene and transcription
Gene : Genbank (Entrez)AA877856 AJ297485 AJ297486 AJ297487 AJ297488
Reference sequence (RefSeq transcript) :SRSNM_000244 NM_130799 NM_130800 NM_130801 NM_130802 NM_130803 NM_130804
Reference transcript : EntrezNM_000244 NM_130799 NM_130800 NM_130801 NM_130802 NM_130803 NM_130804
RefSeq genomic : SRSAC_000054 AC_000143 NC_000011 NG_008929 NT_033903 NW_001838025 NW_925106
RefSeq genomic : EntrezAC_000054 AC_000143 NC_000011 NG_008929 NT_033903 NW_001838025 NW_925106
Consensus coding sequences : CCDS NCBIMEN1
Cluster EST : UnigeneHs.423348 [ SRS ] Hs.423348 [ NCBI ]
Alternative Splicing : Fast-db (Paris)9243
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtO00255 (SRS) O00255 (Expasy) O00255 (Uniprot)
With graphics : InterProO00255
Splice isoforms : VarSplice FASTAO00255(VarSplice FASTA)
Domains : Interpro (SRS)Menin   
Domains : Interpro (EBI)Menin   
Related proteins : CluSTrO00255
Domain families : Pfam SRSMenin (PF05053)   
Domain families : Pfam SangerMenin (PF05053)   
Domain families : Pfam NCBIpfam05053   
Blocks (Seattle)O00255
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD00564
Protein Interaction databases
DIP (DOE-UCLA)O00255
IntAct (EBI)O00255
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIMEN1
SNP : GeneSNP UtahMEN1
SNP : HGBaseMEN1
Genetic variants : HAPMAPMEN1
Somatic Mutations in Cancer : COSMICMEN1 
Mutations and Diseases : HGMDMEN1
Hereditary diseases : OMIM131100    145000   
Hereditary diseases : GENETests131100    145000   
Diseases : Genetic AssociationMEN1
General knowledge
Homologs : HomoloGeneMEN1
Homology/Alignments : Family Browser UCSCMEN1
Phylogenetic Trees/Animal Genes : TreeFamMEN1
Chemical/Protein Interactions : CTD4221
Keywords Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  MAPKKK cascade  four-way junction DNA binding  Y-form DNA binding  chromatin  ossification  leukocyte homeostasis  negative regulation of protein amino acid phosphorylation  osteoblast fate commitment  osteoblast development  DNA binding  chromatin binding  double-stranded DNA binding  soluble fraction  nucleus  cytoplasm  cytosol  DNA repair  chromatin remodeling  response to DNA damage stimulus  cell cycle arrest  negative regulation of cell proliferation  response to UV  embryonic development  response to gamma radiation  nuclear matrix  negative regulation of transcription  histone-lysine N-methyltransferase activity  hemopoiesis  positive regulation of transforming growth factor beta receptor signaling pathway  transcription regulator activity  positive regulation of histone methylation  cleavage furrow  histone methyltransferase complex  positive regulation of apoptosis  protein complex  positive regulation of caspase activity  negative regulation of transcription factor activity  negative regulation of osteoblast differentiation  positive regulation of osteoblast differentiation  negative regulation of cyclin-dependent protein kinase activity  positive regulation of transcription  positive regulation of transcription from RNA polymerase II promoter  negative regulation of JNK cascade  SMAD binding  negative regulation of organ growth  protein N-terminus binding  embryonic skeletal system morphogenesis  positive regulation of cell division  negative regulation of telomerase activity  palate development  maternal process involved in pregnancy  
Keywords Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  MAPKKK cascade  four-way junction DNA binding  Y-form DNA binding  chromatin  ossification  leukocyte homeostasis  negative regulation of protein amino acid phosphorylation  osteoblast fate commitment  osteoblast development  DNA binding  chromatin binding  double-stranded DNA binding  soluble fraction  nucleus  cytoplasm  cytosol  DNA repair  chromatin remodeling  response to DNA damage stimulus  cell cycle arrest  negative regulation of cell proliferation  response to UV  embryonic development  response to gamma radiation  nuclear matrix  negative regulation of transcription  histone-lysine N-methyltransferase activity  hemopoiesis  positive regulation of transforming growth factor beta receptor signaling pathway  transcription regulator activity  positive regulation of histone methylation  cleavage furrow  histone methyltransferase complex  positive regulation of apoptosis  protein complex  positive regulation of caspase activity  negative regulation of transcription factor activity  negative regulation of osteoblast differentiation  positive regulation of osteoblast differentiation  negative regulation of cyclin-dependent protein kinase activity  positive regulation of transcription  positive regulation of transcription from RNA polymerase II promoter  negative regulation of JNK cascade  SMAD binding  negative regulation of organ growth  protein N-terminus binding  embryonic skeletal system morphogenesis  positive regulation of cell division  negative regulation of telomerase activity  palate development  maternal process involved in pregnancy  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Other databaseMEN1 mutation database
Other databaseScientific network
Probes
Probes : ImagenesMEN1 Related clones (RZPD - Berlin)
Literature
PubMed133 Pubmed reference(s) in Entrez
PubGeneMEN1

Bibliography

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Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors.
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Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.
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[Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)]
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PMID 9683585
 
Menin, the product of the MEN1 gene, is a nuclear protein.
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A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1.
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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.
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Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.
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PMID 10092066
 
Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.
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PMID 9989505
 
Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases.
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PMID 9888389
 
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Contributor(s)

Written05-1999Alain Calender

Citation

This paper should be referenced as such :
Calender A . MEN1. Atlas Genet Cytogenet Oncol Haematol. May 1999 .
URL : http://AtlasGeneticsOncology.org/Genes/MEN1ID148.html

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