MEN1

Identity

Hugo	MEN1
Location	11q13

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
Hugo	MEN1
GDB	MEN1
Entrez_Gene	MEN1  4221  multiple endocrine neoplasia I
	Cards
Atlas	MEN1ID148
GeneCards	MEN1
Ensembl	MEN1 [Search_View]   ENSG00000133895 [Gene_View]
Genatlas	MEN1
GeneLynx	MEN1
eGenome	MEN1
euGene	4221
	Genomic and cartography
GoldenPath	MEN1  -  11q13   chr11:64327572-64334764 -  11q13   [Description]    (hg18-Mar_2006)
Ensembl	MEN1 - 11q13 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MEN1
	Gene and transcription
Genbank	AJ297485 [ ENTREZ ]
Genbank	AJ297486 [ ENTREZ ]
Genbank	AJ297487 [ ENTREZ ]
Genbank	AJ297488 [ ENTREZ ]
Genbank	AJ297489 [ ENTREZ ]
RefSeq	NM_000244 [ SRS ]    NM_000244 [ ENTREZ ]
RefSeq	NM_130799 [ SRS ]    NM_130799 [ ENTREZ ]
RefSeq	NM_130800 [ SRS ]    NM_130800 [ ENTREZ ]
RefSeq	NM_130801 [ SRS ]    NM_130801 [ ENTREZ ]
RefSeq	NM_130802 [ SRS ]    NM_130802 [ ENTREZ ]
RefSeq	NM_130803 [ SRS ]    NM_130803 [ ENTREZ ]
RefSeq	NM_130804 [ SRS ]    NM_130804 [ ENTREZ ]
RefSeq	AC_000054 [ SRS ]    AC_000054 [ ENTREZ ]
RefSeq	NC_000011 [ SRS ]    NC_000011 [ ENTREZ ]
RefSeq	NT_033903 [ SRS ]    NT_033903 [ ENTREZ ]
RefSeq	NW_925106 [ SRS ]    NW_925106 [ ENTREZ ]
AceView	MEN1 AceView - NCBI
Unigene	Hs.423348 [ SRS ]    Hs.423348 [ NCBI ]     HS423348 [ spliceNest ]
Fast-db	9243 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O00255 [ SRS]    O00255 [ EXPASY ]     O00255 [ INTERPRO ]
Interpro	IPR007747 Menin [ SRS ]    IPR007747 Menin [ EBI ]
CluSTr	O00255
Pfam	PF05053 Menin [ SRS ]    PF05053 Menin [ Sanger ]    pfam05053 [ NCBI-CDD ]
Blocks	O00255
HPRD	00564
	Protein Interaction databases
DIP	O00255
IntAct	O00255
	Polymorphism : SNP, mutations, diseases
OMIM	131100;145000    [ map ]
GENECLINICS	131100;145000
SNP	MEN1 [dbSNP-NCBI]
SNP	NM_000244 [SNP-NCI]
SNP	NM_130799 [SNP-NCI]
SNP	NM_130800 [SNP-NCI]
SNP	NM_130801 [SNP-NCI]
SNP	NM_130802 [SNP-NCI]
SNP	NM_130803 [SNP-NCI]
SNP	NM_130804 [SNP-NCI]
SNP	MEN1 [GeneSNPs - Utah]  MEN1] [HGBASE - SRS]
HAPMAP	MEN1 [HAPMAP]
COSMIC	MEN1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	MEN1
	General knowledge
Family Browser	MEN1 [UCSC Family Browser]
SOURCE	NM_000244
SOURCE	NM_130799
SOURCE	NM_130800
SOURCE	NM_130801
SOURCE	NM_130802
SOURCE	NM_130803
SOURCE	NM_130804
SMD	Hs.423348
SAGE	Hs.423348
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GO	DNA binding [Amigo]  DNA binding
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	nucleus [Amigo]  nucleus
GO	cytosol [Amigo]  cytosol
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	histone methylation [Amigo]  histone methylation
GO	transcription regulator activity [Amigo]  transcription regulator activity
GO	cleavage furrow [Amigo]  cleavage furrow
GO	histone methyltransferase complex [Amigo]  histone methyltransferase complex
GO	positive regulation of transcription [Amigo]  positive regulation of transcription
PubGene	MEN1
TreeFam	MEN1
CTD	4221 [Comparative ToxicoGenomics Database]
	Other databases
Other database	MEN1 mutation database
Other database	Scientific network
	Probes
Probe	MEN1 Related clones (RZPD - Berlin)
	PubMed
PubMed	99 Pubmed reference(s) in LocusLink

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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Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1.

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PMID 9215690

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American journal of human genetics. 1998 ; 62 (2) : 232-244.

PMID 9463336

[Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)]

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Annales d'endocrinologie. 1998 ; 59 (6) : 444-451.

PMID 10189986

Genetic testing in multiple endocrine neoplasia and related syndromes.

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PMID 9666051

Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.

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PMID 9843042

Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.

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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

A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1.

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PMID 9510467

Characterization of the mouse Men1 gene and its expression during development.

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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, Nordenskjˆld 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.

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PMID 9709921

Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin.

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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)

Written	05-1999	Alain 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:24:53 2008