Review on MEN1 (multiple endocrine neoplasia I), with data on DNA, on the protein encoded, and where the gene is implicated

Calender, A

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

 
 
 
 
 
 
 
Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(2)  
 
75 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
OPEN ACCESS JOURNAL AT INIST-CNRS 
MEN1 multiple endocrine neoplasia I 
Alain Calender 
Service de génétique moléculaire et médicale, hôpital Edouard-Herriot, bâtiment B7, 5, place d'Arsonval, 
69437 Lyon 03, France (AC) 
 
Published in Atlas Database: May 1999 
Online updated version : http://AtlasGeneticsOncology.org/Genes/MEN1ID148.html 
DOI: 10.4267/2042/37509 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
HGNC (Hugo): MEN1 
Location: 11q13 
Note: Mutiple Endocrine neoplasia type 1: MEN1 (or 
Wermer syndrome) is an inherited predisposition to 
parathyroid, endocrine pancreas, pituitary, adrenal a d 
neuroendocrine tumors and segregates as an autosomal 
dominant disease with high penetrance. 
DNA/RNA 
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. 
 
 
Structure of the MEN1 gene (The European Consortium on MEN1, 1997).
MEN1 multiple endocrine neoplasia I Calender A 
 
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(2)  
 
76 
Localisation 
Primarily localized in the nucleus and could translte 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 mutatn s 
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 
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 notdiffer 
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,  
MEN1 multiple endocrine neoplasia I Calender A 
 
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(2)  
 
77 
hyeperaldoseronism, Cushing syndrome, 
hyperprolactinemia, acromegaly; more than 30-50% of 
digestive neuroendocrine tumors and those localized in 
thymus and bronchi have a metastatic potential. 
References 
WERMER P. Genetic aspects of adenomatosis of endocrine 
glands. Am J Med. 1954 Mar;16(3):363-71 
Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld 
M. Multiple endocrine neoplasia type 1 gene maps to 
chromosome 11 and is lost in insulinoma. Nature. 1988 Mar 
3;332(6159):85-7 
Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, 
Skogseid B, Oberg K, Werner S, Nordenskjöld M. Localization 
of the MEN1 gene to a small region within chromosome 11q13 
by deletion mapping in tumors. Proc Natl Acad Sci U S A. 1990 
Mar;87(5):1968-72 
Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-
Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, 
Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, 
Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, 
Burns AL, Marx SJ. Germline mutations of the MEN1 gene in 
familial multiple endocrine neoplasia type 1 and related states. 
Hum Mol Genet. 1997 Jul;6(7):1169-75 
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. 
Positional cloning of the gene for multiple endocrine neoplasia-
type 1. Science. 1997 Apr 18;276(5311):404-7 
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. Identification of 
the multiple endocrine neoplasia type 1 (MEN1) gene. The 
European Consortium on MEN1. Hum Mol Genet. 1997 
Jul;6(7):1177-83 
Mayr B, Apenberg S, Rothämel T, von zur Mühlen A, Brabant 
G. Menin mutations in patients with multiple endocrine 
neoplasia type 1. Eur J Endocrinol. 1997 Dec;137(6):684-7 
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. Germline mutations of the MEN1 gene 
in Japanese kindred with multiple endocrine neoplasia type 1. 
Jpn J Cancer Res. 1997 Nov;88(11):1029-32 
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. 
Characterization of mutations in patients with multiple 
endocrine neoplasia type 1. Am J Hum Genet. 1998 
Feb;62(2):232-44 
Calender A. Genetic testing in multiple endocrine neoplasia 
and related syndromes. Forum (Genova). 1998 Apr-
Jun;8(2):146-59 
Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, 
Mignon M. [Clinicogenetic study of MEN1: recent 
physiopathological data and clinical applications. Study Group 
of Multiple Endocrine Neoplasia (GENEM)]. Ann Endocrinol 
(Paris). 1998;59(6):444-51 
Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, 
Ito K, Shingu K, Kobayashi S, Amano J, Fukushima Y. Novel 
V184E MEN1 germline mutation in a Japanese kindred with 
familial hyperparathyroidism. Am J Med Genet. 1998 Nov 
16;80(3):221-2 
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, et al. 
Germ-line mutation analysis in patients with multiple endocrine 
neoplasia type 1 and related disorders. Am J Hum Genet. 1998 
Aug;63(2):455-67 
Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, 
Collins FS, Chandrasekharappa SC. Menin, the product of the 
MEN1 gene, is a nuclear protein. Proc Natl Acad Sci U S A. 
1998 Feb 17;95(4):1630-4 
Kishi M, Tsukada T, Shimizu S, Futami H, Ito Y, Kanbe M, 
Obara T, Yamaguchi K. A large germline deletion of the MEN1 
gene in a family with multiple endocrine neoplasia type 1. Jpn J 
Cancer Res. 1998 Jan;89(1):1-5 
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. Characterization of the mouse Men1 gene and its 
expression during development. Oncogene. 1998 Nov 
12;17(19):2485-93 
Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, 
Nordenskjöld M, Pearce CJ, Carmichael D, Larsson C, Harris 
PE. A family with isolated hyperparathyroidism segregating a 
missense MEN1 mutation and showing loss of the wild-type 
alleles in the parathyroid tumors. Am J Hum Genet. 1998 
Nov;63(5):1544-9 
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, et al. Mutation analysis of the 
MEN1 gene in multiple endocrine neoplasia type 1, familial 
acromegaly and familial isolated hyperparathyroidism. J Clin 
Endocrinol Metab. 1998 Aug;83(8):2621-6 
Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, 
Park SY, Saggar S, Chandrasekharappa SC, Collins FS, 
Spiegel AM, Marx SJ, Burns AL. Menin interacts with the AP1 
transcription factor JunD and represses JunD-activated 
transcription. Cell. 1999 Jan 8;96(1):143-52 
Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC, 
Pham TA, Lubensky IA. Nuclear/cytoplasmic localization of the 
multiple endocrine neoplasia type 1 gene product, menin. Lab 
Invest. 1999 Mar;79(3):301-10 
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. Mutation analysis of the MEN1 gene 
in Belgian patients with multiple endocrine neoplasia type 1 
and related diseases. Hum Mutat. 1999;13(1):54-60 
This article should be referenced as such: 
Calender A. MEN1 multiple endocrine neoplasia I. Atlas Genet 
Cytogenet Oncol Haematol. 1999; 3(2):75-77. 


MEN1 (multiple endocrine neoplasia I)

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MEN1 (multiple endocrine neoplasia I)

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