Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

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Molecular and Cellular Endocrinology

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Review

Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4)

Rajesh V. Thakker ⇑
Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital,
Headington, Oxford OX3 7LJ, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more
Available online xxxx endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant dis-
orders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previ-
Keywords: ously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during
Parathyroid transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to
Pancreatic islet cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence
Pituitary
of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and
Tumors
Neuroendocrine tumors
anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma
Histone methylation (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the
occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas,
medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and
MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior
pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs.
This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene
causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which
has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold
protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone
methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that
trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes
such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation
3–9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional
activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent
with Knudson’s two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 muta-
tions has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high
risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is
caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which
is activated by H3K4 methylation.
Ó 2013 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Multiple endocrine neoplasia type 1 (MEN1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. MEN1 mutations in sporadic non-MEN1 endocrine tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.5. MEN1 mutations in hereditary endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.6. Genetic testing and screening in MEN1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.6.1. MEN1 mutational analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.7. Detection of MEN1 tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

⇑ Tel.: +44 1865 857501; fax: +44 1865 857502.

E-mail address: rajesh.thakker@ndm.ox.ac.uk

0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mce.2013.08.002

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
2 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

2.8. MEN1 phenocopies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Function of menin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Menin and epigenetic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Multiple endocrine neoplasia type 4 (MEN4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction either may be inherited as autosomal-dominant syndromes (Thak-

Multiple endocrine neoplasia (MEN) is characterized by the
occurrence of tumors involving two or more endocrine glands
within a single patient (Thakker, 2010). The disorder has previ-
ously been referred to as multiple endocrine adenopathy or the
pluriglandular syndrome. However, glandular hyperplasia and
malignancy may also occur in some patients, and the term multiple
endocrine neoplasia is now preferred. Four major forms of MEN are
recognized and referred to as types 1–4 (MEN1–MEN4), and each
form is characterized by the development of tumors within specific
endocrine glands (Table 1) (Thakker, 1998). All these forms of MEN
ker, 1998) or may occur sporadically; that is, without a family his-
tory (Thakker, 2010). However, this distinction between sporadic
and familial cases may sometimes be difficult, because in some
sporadic cases, a family history may be absent because the parent
with the disease may have died before symptoms developed.
MEN1, which is also referred to as Wermer’s syndrome (Thakker,
1998) is characterized by the combined occurrence of tumors of
the parathyroid glands, the pancreatic islet cells, and the anterior
pituitary. In addition to these tumors, adrenal cortical tumors, car-
cinoid, facial angiofibromas, collagenomas, and lipomatous tumors
have been described in patients with MEN1 (Trump et al., 1996).

Table 1
Multiple endocrine neoplasia syndromes and their characteristic tumors and associated genetic abnormalities.

Type (chromosome location) Tumors (estimated penetrance) Gene; most frequently mutated codons
MEN1 (11q13) Parathyroid adenoma (90%) MEN1
Entero-pancreatic tumor (30–70%) 83/84, 4-bp del (4%)
– Gastrinoma (40%) 119, 3-bp del (3%)
– Insulinoma (10%) 209–211, 4-bp del (8%)
– Non-functioning & PPoma (20–55%) 418, 3-bp del (4%)
– Glucagonoma (<1%) 514–516, del or ins (7%)
– VIPoma (<1%) Intron 4 ss, (10%)
Pituitary adenoma (30–40%)
– Prolactinoma (20%)
– Somatotrophinoma (10%)
– Corticotrophinoma (<5%)
– Non-functioning (<5%)
Associated Tumors/
– Adrenal cortical tumor (40%)
– Phaeochromocytoma (<1%)
– Brochopulmonary NET (2%)
– Thymic NET (2%)
– Gastric NET (10%)
– Lipomas (30%)
– Angiofibromas (85%)
– Collagenomas (70%)
– Meningiomas (8%)

MEN2 (10 cen-10q11.2)

MEN2A MTC (90%) RET
Phaeochromocytoma (50%) 634, missense
Parathyroid adenoma (20–30%) e.g. Cys ? Arg (85%)
MTC only MTC (100%) RET
618, missense (>50%)
MEN2B (also known as MEN3) MTC (>90%) RET
Phaeochromocytoma (40–50%) 918, Met ? Thr (>95%)
Associated abnormalities (40–50%)
Mucosal neuromas
Marfanoid habitus
Medullated corneal nerve fibers
Megacolon
MEN4 (12p13) Parathyroid adenomaa CDKN1B
Pituitary adenomaa No common mutations identified to date
Reproduction organ tumorsa (e.g. testicular cancer, neuroendocrine cervical carcinoma)
Adrenal + renal tumorsa

Autosomal-dominant inheritance of the MEN syndromes has been established. del, deletion; ins, insertion; PPoma, pancreatic polypeptide–secreting tumor; VIPoma,
vasoactive intestinal polypeptide–secreting tumor; MTC, Medullary Thyroid Cancer. Adapted from Thakker RV: Clinical Practice Guidelines for Multiple Endocrine Neoplasia
Type 1 (MEN1). J Clin Endocrinol Metab 97: 2990–3011, Ó2012. The Endocrine Society (Thakker et al., 2012).
a
Insufficient numbers reported to provide prevalence information.

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 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx 3

However, in MEN2, which is also called Sipple’s syndrome and was

previously referred to as MEN2A, medullary thyroid carcinoma
(MTC) occurs in association with phaeochromocytoma and para-
thyroid tumors (Thakker, 1998). In MEN3, which was previously
referred to as MEN2B, MTC and pheochromocytoma occur in asso-
ciation with a marfanoid habitus, mucosal neuromas, medullated
corneal fibers, and intestinal autonomic ganglion dysfunction lead-
ing to megacolon (Thakker, 1998), with rare occurrence of parathy-
roid tumors. MTC may also occur as the sole manifestation of the
MEN2 syndrome, and this variant is referred to as MTC-only. In
MEN4, which is also referred to as MENX, patients develop para-
thyroid and anterior pituitary tumors, which may occur in associ-
ation with tumors of the reproductive organs, adrenals and
kidneys. This review will focus on the clinical features, genetics
and epigenetics of the MEN1 and MEN4 syndromes.
Fig. 1. Basis for a diagnosis of MEN1 in individuals. A diagnosis of MEN1 based on
clinical and familial criteria may be confounded by the occurrence of phenocopies.
(Reproduced with permission from Turner et al. (2010).) (Turner et al., 2010).
2. Multiple endocrine neoplasia type 1 (MEN1)

islet tumors, gastrinomas and foregut carcinoids (Dean et al.,

2.1. Clinical features
The incidence of MEN1 has been estimated from randomly cho-
sen postmortem studies to be 0.25% and to be 1–18% among pa-
tients with primary hyperparathyroidism, 16–38% among
patients with gastrinomas, and less than 3% among patients with
pituitary tumors (Thakker, 2010). The disorder affects all age
groups, with a reported age range of 5–81 years, with clinical
and biochemical manifestations of the disorder having developed
in 80% and more than 98% of patients, respectively, by the fifth dec-
ade (Thakker et al., 1989, 2012; Trump et al., 1996). The clinical
manifestations of MEN1 are related to the sites of tumors and to
their products of secretion. Parathyroid tumors, resulting in pri-
mary hyperparathyroidism, are the most common feature of
MEN1 and occur in 95% of MEN1 patients (Benson et al., 1987;
Brandi et al., 2001; Calender et al., 1995; Marx et al., 1998; Trump
et al., 1996). Pancreatic islet tumors, which are also referred to as
pancreatic neuroendocrine tumors (NETs) consist of gastrinomas,
insulinomas, pancreatic polypeptidomas (PPomas), glucagonomas,
vaso-active intestinal polypeptidomas (VIPomas) and non-func-
tioning tumors and these occur in 40% of MEN1 patients; and
anterior pituitary tumors, consisting of prolactinomas, somatotro-
phinomas, corticotrophinomas, and non-functioning adenomas,
occur in 30% of patients (Benson et al., 1987; Calender et al.,
1995; Marx et al., 1998; Trump et al., 1996). In addition, some
MEN1 patients may also develop adrenocortical tumors, lipomas,
carcinoid tumors, facial angiofibromas and collagenomas (Bassett
et al., 1998; Brandi et al., 2001; Calender et al., 1995; Marx et al.,
1998; Trump et al., 1996). Parathyroid tumors are the first mani-
festation of MEN1 in more than 85% of patients, and in the remain-
ing fewer than 15% of patients, the first manifestation may be an
insulinoma or a prolactinoma (Thakker et al., 1989; Trump et al.,
1996). Combinations of these affected glands and their pathologic
features (for example, hyperplasia or single or multiple adenomas
of the parathyroid glands) have been reported to differ in members
of the same family (Thakker et al., 1989; Trump et al., 1996) and
even between identical twins (Flanagan et al., 1996). MEN1 is
inherited as an autosomal-dominant disorder in such families,
but a non-familial (i.e., sporadic) (Trump et al., 1996) form may
have developed in 8–14% of patients with MEN1, and molecular ge-
netic studies have confirmed the occurrence of de novo mutations
of the MEN1 gene in approximately 10% of patients with MEN1
(Bassett et al., 1998). In the absence of treatment, these tumors
have been observed to be associated with an earlier mortality in
patients with MEN1 (Burgess et al., 1998). Studies of MEN1-related
mortality have demonstrated that 28–46% of deaths are directly re-
lated to MEN1, most commonly as a result of malignant pancreatic
2000). In addition, these deaths occur at a significantly younger
age than those occurring in unaffected individuals (Dean et al.,
2000). Furthermore, a recent multicentre study from France and
Belgium has suggested that 70% individuals with MEN1 currently
die of causes directly related to MEN1 (Goudet et al., 2010). In par-
ticular, malignant pancreatic islet tumors and thymic carcinoid tu-
mors were associated with a marked increased in risk of death
(Hazard ratio >3, P < 0.005) (Goudet et al., 2010).
A diagnosis of MEN1 may be established in an individual by one
of three criteria (Fig. 1). Thus, MEN1 may be clinically diagnosed in
an individual on the basis of the occurrence of two or more MEN1-
associated endocrine tumors (Fig. 1) (Thakker et al., 2012; Turner
et al., 2010). In addition, a diagnosis of familial MEN1 is established
for an individual who has the occurrence of one of the MEN1-asso-
ciated tumors and is a first degree relative of a patient with a clin-
ical diagnosis of MEN1. Finally, a genetic diagnosis of MEN1 is
made on identification of a germline MEN1 mutation in an individ-
ual, who may be asymptomatic and has not yet developed any of
the serum biochemical or radiological abnormalities indicative of
tumor development (Fig. 2) (Turner et al., 2010).
2.2. Treatment
The treatment for each type of MEN1 associated endocrine tu-
mor is generally similar to that for the respective tumors occurring
in non-MEN1 patients. However, the treatment outcomes of
MEN1-associated tumors are not as successful as those in non-
MEN1 patients, for several reasons. First, MEN1-associated tumors,
with the exception of pituitary NETs, are usually multiple, thereby
making it difficult to achieve a successful surgical cure. For exam-
ple, MEN1 patients often develop multiple submucosal duodenal
gastrinomas, thereby reducing surgical cure rates compared with
similar sporadic solitary tumors, such that only 15% of MEN1 pa-
tients, compared to 45% of non-MEN1 patients, are free of disease
immediately after surgery, and at 5 years this decreased to 5% in
MEN1 patients, compared to 40% in non-MEN1 patients (Brandi
et al., 2001; Imamura et al., 2011; Norton et al., 1999; Norton
and Jensen, 2007; Tonelli et al., 2006). MEN1 patients also develop
multiple parathyroid tumors, and subtotal parathyroidectomy has
resulted in persistent or recurrent hypercalcaemia within 10 years
in 20–60% of MEN1 patients, as opposed to 4% in non-MEN1 pa-
tients (Brandi et al., 2001; Schreinemakers et al., 2011; Waldmann
et al., 2010). Secondly, occult metastatic disease is more prevalent
in MEN1 patients with NETs than in patients with sporadic endo-
crine tumors. For example, metastases are present in up to 50%
of patients with MEN1-associated insulinomas, whereas <10% of

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
4 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

Fig. 2. Detection of MEN1 mutation in exon 3 in family 8/89 by restriction enzyme analysis. DNA sequence analysis of individual II.1 revealed a 1-bp deletion at the second
position (GGT) of codon 214 (A). The deletion has caused a frameshift that continues to codon 223 before a stop codon (TGA) is encountered in the new frame. The 1-bp
deletion results in the loss of an MspI restriction enzyme site (C/CGG) from the normal (wild-type, WT) sequence (A), and this finding has facilitated detection of this mutation
in the other affected members (II.4, III.3, and III.4) of this family (B). The mutant (m) polymerase chain reaction product is 190 bp, whereas the WT products are 117 and 73 bp
(C). The affected individuals were heterozygous, and the unaffected members were homozygous for the WT sequence. Individuals III.6 and III.10, who are 40 and 28 years old,
respectively, are mutant gene carriers who are clinically and biochemically normal because of the age-related penetrance of this disorder (Fig. 5). These individuals would still
require screening (Fig. 6) by clinical, biochemical, and radiologic assessment because they still have a residual risk (i.e., 100% – age-related penetrance) of 2% and >13%,
respectively, of tumors developing by age 60 years. Individuals are represented as male (square); female (circle); unaffected (open); affected with parathyroid tumors (solid
upper right quadrant), gastrinoma (solid lower right quadrant), or prolactinoma (solid upper left quadrant); and unaffected mutant gene carriers (dot in the middle of the
open symbol). Individual I.2, who is dead but was known to be affected (tumor details not known), is shown as a solid symbol. The age is indicated below for each individual
at diagnosis or at the time of the last biochemical screening. The standard size marker (S) in the form of the 1-kb ladder is indicated. Cosegregation of this mutation with
MEN1 in family 8/89 and its absence in 110 alleles from 55 unrelated normal individuals (N1–3 shown) indicate that it is not a common DNA sequence polymorphism.
(Adapted from Bassett JHD, Forbes SA, Pannett AAJ, et al.: Characterization of mutations in patients with multiple endocrine neoplasia type 1 (MEN1). Am J Hum Genet 62:
232–244, 1998, with permission.) (Bassett et al., 1998).

non-MEN1 insulinomas metastasise (Akerstrom and Hellman,
2007). Thirdly, MEN1-associated tumors may be larger, more
aggressive, and resistant to treatment. For example, 85% of ante-
rior pituitary tumors in MEN1 patients, as opposed to 64% in non-
MEN1 patients are macroadenomas at the time of diagnosis; 30%
of anterior pituitary tumors in MEN1 patients have invaded sur-
rounding tissue (Hardy classification grades III and IV), compared
to 10% in non-MEN1 patients; and >45% of anterior pituitary NETs
in MEN1 patients had persistent hormonal over-secretion follow-
ing appropriate medical, surgical and radiotherapy treatment,
compared with between 10% and 40% in non-MEN1 patients (Fer-
nandez et al., 2010; Trouillas et al., 2008; Verges et al., 2002). Thus,
the treatment of MEN1-associated tumors is difficult requires a
multi-disciplinary team of experts.
2.3. Genetics
The MEN1 gene is located on chromosome 11q13 and consists of
10 exons (Fig. 3) that encode a 610-amino acid protein, referred to
as menin. Menin is ubiquitously expressed and is predominantly a
nuclear protein in non-dividing cells. Mutations of the MEN1 gene
(Figs. 2 and 3) have been characterized, and a total of 1336 muta-
tions (1133 germline and 203 somatic mutations) were reported in
the first decade following the identification of the gene (Lemos and
Thakker, 2008). The 1133 germ-line mutations of the MEN1 gene,
which consist of 459 different mutations are scattered throughout
the entire 1.830 bp coding region and splice sites of the MEN1 gene
(Agarwal et al., 1997; Bassett et al., 1998; Chandrasekharappa
et al., 1997; Lemos and Thakker, 2008; The European Consortium
on MEN1, 1997). Approximately 23% are nonsense mutations,
around 41% are frameshift deletions or insertions, 6% are in-frame
deletions or insertions, 9% are splice-site mutations, and 20% are
missense mutations, and 1% are whole or particular gene deletions
(Fig. 4) (Lemos and Thakker, 2008). More than 10% of the MEN1
mutations arise de novo and may be transmitted to subsequent
generations (Bassett et al., 1998; Lemos and Thakker, 2008; Zable-
wska et al., 2003). It also is important to note that between 5% and
10% of patients with MEN1 may not harbor mutations in the coding

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx 5

Fig. 3. Schematic representation of the genomic organization of the MEN1 gene, its encoded protein (menin) and regions that interact with other proteins. (A) The human
MEN1 gene consists of 10 exons that span more than 9 kb of genomic DNA and encodes a 610-amino acid protein. The 1.83 kb coding region (indicated by shaded region) is
organized into 9 exons (exons 2–10) and 8 introns (indicated by a line but not to scale). The sizes of the exons (boxes) range from 41 to 1297 bp, and that of the introns range
from 80 to 1564 bp. The start (ATG) and stop (TGA) codons in exons 2 and 10, respectively, are indicated. Exon 1, the 50 part of exon 2, and the 30 part of exon 10 are
untranslated (indicated by open boxes). The promoter region is located within a few 100 bp upstream of exon 2. The sites of the nine germline mutations (I–IX) that occur
with a frequency >1.5% (Table 2) are shown and their respective frequencies (scale shown on the right) are indicated by the vertical lines above the gene. These germline
mutations, which collectively represent 20.6% of all reported germline mutations, are: I – c.249_252delGTCT; II – c.292C>T; III – c.358_360delAAG; IV4 – c.628_631delACAG;
V – c.7849G>A; VI – c.1243C>T; VII – c.1378C>T; VIII – c.1546delC; IX – c.1546_1547insC. The locations of the 24 polymorphisms (a–x, Table 4) are illustrated. (B) Menin has
three nuclear localization signals (NLSs) at codons 479–497 (NLS1), 546–572 (NLSa) and 588–608 (NLS2), indicated by closed boxes, and five putative guanosine
triphosphatase (GTPase) sites (G1–G5) indicated by closed bars. (C) Menin regions that have been implicated in the binding to different interacting proteins (Table 6) are
indicated by open boxes. These are JunD (codons 1–40, 139–242, 323–428); nuclear factor-kappa B (NF-jB) (codons 305–381); Smad3 (codons 40–278, 477–610); placenta
and embryonic expression, pem (codons 278–476); NM23H1 (codons 1–486); a subunit of replication protein A (RPA2) (codons 1–40, 286–448); NMHC II-A (codons 154–
306); FANCD2 (codons 219–395); mSin3A (codons 371–387); HDAC1 (codons 145–450); ASK (codons 558–610) and CHES1 (codons 428–610). The regions of menin that
interact with GFAP, vimentin, Smad 1/5, Runx2, MLL-histone methyltransferase complex and estrogen receptor-alpha remain to be determined. (Reproduced from Lemos MC,
Thakker RV: Multiple Endocrine Neoplasia Type 1 (MEN1): Analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 29: 22–32,
2008, with permission.) (Lemos and Thakker, 2008).

region of the MEN1 gene (Agarwal et al., 1997; Bassett et al., 1998;
Chandrasekharappa et al., 1997; Lemos and Thakker, 2008; The
European Consortium on MEN1, 1997), and that these individuals
may have whole gene deletions or mutations in the promoter or
untranslated regions, which remain to be investigated. One study
showed that approximately 33% of patients who do not have muta-
tions within the coding region have large deletions involving com-
plete exons (Cavaco et al., 2002). Such abnormalities will not be
easily detected by DNA sequence analysis.
Most (75%) of the MEN1 mutations are inactivating (Lemos and
Thakker, 2008) and are consistent with those expected in a tumor-
suppressor gene. The mutations not only are diverse in their types
but are also scattered throughout the 1830-bp coding region of the
MEN1 gene with no evidence for clustering as observed in MEN2
(Table 1). However, some of the mutations have been observed
to occur several times in unrelated families (Fig. 3 and Table 2).
Mutations at nine sites in the MEN1 gene accounted for over 20%
of all the germ-line mutations (Table 2). Of these nine types of
mutations, five are deletional and insertional mutations involving
codons 83 and 84 (nt359 del 4), 120 (Lys[K]120 del), 210–211
(nt 738 del 4), and codons 514–516 (nt 1656–7 del or ins C); one
is a novel acceptor splice site in intron 4, and three are nonsense
mutations (Arg98Stop, Arg415Stop, and Arg460Stop) (Lemos and
Thakker, 2008). These mutations at these nine different sites could
be considered to represent potential ‘‘hot’’ spots (Table 2). Such
deletional and insertional hot spots may be associated with DNA
sequence repeats, which may consist of long tracts of either single
nucleotides or shorter elements ranging from dinucleotides to
octanucleotides (Bassett et al., 1998). The DNA sequences in the
vicinity of codons 83 and 84 in exon 2, and codons 210–211 in
exon 3, contain CT and CA dinucleotide repeats, respectively, flank-
ing the 4-bp deletions; this finding would be consistent with a rep-
lication-slippage model in which misalignment of the dinucleotide
repeat takes place during replication, followed by excision of the 4-
bp single-stranded loop (Bassett et al., 1998). A similar replication-
slippage model may also be involved at codons 119 and 120, each
of which consists of AAG nucleotides encoding a lysine (K) residue.
The deletions and insertions of codon 516 involve a poly(C)7 tract,
and a slipped-strand mispairing model also is the most likely
mechanism to be associated with this mutational hot spot (Bassett
et al., 1998; Lemos and Thakker, 2008). Thus, the MEN1 gene ap-
pears to contain DNA sequences that may render it susceptible to
deletional and insertional mutations.
Correlations between MEN1 mutations and clinical manifesta-
tions of the disorder appear to be absent. For example, a detailed
study of five unrelated families with the same 4-bp deletion in

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
6 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

50 Table 3
Multiple endocrine neoplasia type 1 – associated tumors in five unrelated families
Germline, n=653 with a 4-bp deletion at codons 210 and 211.
Somatic, n=194 Tumors Family
40
1 2 3 4 5
Parathyroid + + + + +
30 Gastrinoma +  + + +
Percent

Insulinoma  +   
Glucagonoma     +
Prolactinoma  + + + +
20 Carcinoid +    

+, Presence; , Absence of tumors.

Adapted from Thakker RV: Multiple endocrine neoplasia—syndromes of the twen-
10 tieth century. J Clin Endocrinol Metab 83: 2617–2620, Ó1998. The Endocrine Society
(Thakker, 1998).

0
ns fs del/ins sp ms Table 4
Polymorphisms of the MEN1 gene.
ns = nonsense sp = splice site
fs = frame-shift ms = missense Polymorphisma DNA sequence Exon Codon change Allele
del/ins = deletions / insertions *P<0.001 changeb frequencyc
a c.-533T>A 1 – 0.32
Fig. 4. Frequency of germ-line and somatic MEN1 mutations. A total of 1133 germ-
b c.-533T>C 1 – 0.12
line mutations and 203 somatic mutations have been reported (Agarwal et al.,
c c.-39C>G Intron 1 – 0.20
1997), and these are of diverse types (e.g., nonsense, frameshifts, deletions,
d n/a 2 Leu10Leu n/a
insertions, splice-site, and missense mutations). The frequencies of each type of
e c.435C>T 2 Ser145Ser 0.01
mutation in the germ-line and somatic groups are similar, with the exception of the
f c.445+183G>A Intron 2 – 0.05
missense mutations, which are found more frequently in tumors (i.e., the somatic
g c.446127A>T Intron 2 – n/a
group). (Reproduced from Lemos MC, Thakker RV: Multiple Endocrine Neoplasia
h c.44658C>T Intron 2 – 0.01
Type 1 (MEN1): Analysis of 1336 mutations reported in the first decade following
i c.512G>A 3 Arg171Gln 0.01
identification of the gene. Hum Mutat 29: 22–32, 2008, with permission.) (Lemos
j c.768T>C 4 Leu256Leu 0.01
and Thakker, 2008).
k c.824+31T>C Intron 5 – n/a
l c.9133C>G Intron 6 – 0.02
m c.1026G>A 7 Ala342Ala 0.01
Table 2 n c.105092C>T Intron 7 – 0.03
MEN1 germline mutations occurring in over 1.5% of affected families. o c.10503C>G Intron 7 – 0.02
p c.1101A>C 8 Val367Val n/a
Mutationa DNA sequence Exon Codon Predicted Frequency
q c.1254C>T 9 Asp418Asp 0.42
changeb effectc (%)d
r c.1296G>A 9 Leu432Leu 0.01
I c.249_252delGTCT 2 83–84 fs 4.5 s c.1299T>C 9 His433His 0.01
II c.292C>T 2 98 ns, 1.5 t c.1350+103G>C Intron 9 – 0.42
Arg98Stop u c.1434C>T 10 Gly478Gly n/a
III c.358_360delAAG 2 120 if 1.7 v c.1621G>A 10 Ala541Thr 0.04
IV c.628_631delACAG 3 210– fs 2.5 w c.1764G>A 10 Lys588Lys n/a
211 x c.1833305_1833 10 – 0.05
V c.784-9G>A Intron – sp 1.9 307delCTC
4
VI c.1243C>T 9 415 ns, 1.5 n/a – Data not available. (From Lemos M and Thakker RV: Multiple Endocrine
Arg415Stop Neoplasia Type 1 (MEN1): Analysis of 1336 Mutations Reported in the First Decade
VII c.1378C>T 10 460 ns, 2.6 Following Identification of the Gene. Hum Mutat 29: 22–32, 2008, with permission).
Arg460Stop (Lemos and Thakker, 2008).
a
VIII c.1546delC 10 516 fs 1.8 Polymorphism letter as referred to in Fig. 3.
b
IX c.1546_1547insC 10 516 fs 2.7 Polymorphisms are numbered in relation to the MEN1 cDNA reference sequence
(GenBank accession number NM_130799.1), whereby nucleotide +1 corresponds to
a
Mutation number as referred to in Fig. 3. the A of the ATG-translation initiation codon.
b c
Mutations are numbered in relation to the MEN1 cDNA reference sequence Frequency presented in first literature report.
(GenBank accession number NM_130799.1), whereby nucleotide +1 corresponds to
the A of the ATG-translation initiation codon.
c
fs – frameshift mutation; ns – nonsense mutation; sp – splice site mutation; if –
in-frame mutation. of seven unrelated families with the same g ? a novel acceptor
d
Frequencies based on 1133 reported MEN1 independent germline mutations. splice-site mutation in intron 4 revealed a similarly wide range
(From Lemos M and Thakker RV: Multiple Endocrine Neoplasia Type 1 (MEN1): of MEN1-associated tumors and a lack of genotype/phenotype cor-
Analysis of 1336 Mutations Reported in the First Decade Following Identification of relation. The apparent lack of genotype/phenotype correlation,
the Gene. Hum Mutat 29: 22–32, 2008, with permission) (Lemos and Thakker,
which contrasts with the situation in MEN2 (Table 1), together
2008).
with the wide diversity of mutations in the 1830-bp coding region
of the MEN1 gene, makes mutational analysis for diagnostic pur-
poses in MEN1 more difficult than that for MEN2 (Thakker, 1998).
codons 210 and 211 (Table 3) revealed a wide range of MEN1-asso- A total of 24 different polymorphisms (12 in the coding region
ciated tumors (Bassett et al., 1998; Lemos and Thakker, 2008; [10 synonymous and 2 non synonymous], 9 in the introns, and 3
Thakker, 1998); all affected family members had parathyroid tu- in the untranslated regions) of the MEN1 gene have been reported
mors, but members of families 1, 3, 4, and 5 had gastrinomas, (Fig. 3 and Table 4) (Lemos and Thakker, 2008). It is important to
whereas members of family 2 had insulinomas. In addition, prolac- recognize the occurrence of these polymorphisms as they need to
tinomas occurred in members of families 2, 3, 4, and 5 but not in be distinguished from mutations when performing analysis for ge-
family 1, which was affected with carcinoid tumors. Another study netic diagnosis.

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx
More than 90% of tumors from MEN1 patients have loss of het-
erozygosity (LOH), and this has generally been taken as evidence
that the MEN1 gene acts as a tumor-suppressor gene, consistent
with Knudson’s two-hit hypothesis (Friedman et al., 1989; Larsson
et al., 1988; Thakker et al., 1989). However, this LOH represents
only one mechanism by which the second hit may occur, with
the other mechanisms being intragenic deletions and point muta-
tions. MEN1 tumors (e.g., parathyroids, insulinoma, and lipoma)
that do not have LOH have been shown to harbor different somatic
and germ-line mutations of the MEN1 gene (Fig. 4) (Pannett and
Thakker, 2001), and this is consistent with the Knudson two-hit
hypothesis (Knudson et al., 1973).
2.4. MEN1 mutations in sporadic non-MEN1 endocrine tumors
Parathyroid, pancreatic islet cell, and anterior pituitary tumors
may occur either as part of MEN1 or more commonly as sporadic,
nonfamilial tumors. Tumors from patients with MEN1 have been
observed to harbor the germ-line mutation together with a somatic
LOH involving chromosome 11q13 (Friedman et al., 1989; Larsson
et al., 1988; Thakker et al., 1989, 1993), or point mutations, as ex-
pected from Knudson’s model (Pannett and Thakker, 2001) and the
proposed role of the MEN1 gene as a tumor suppressor. However,
LOH involving chromosome 11q13, which is the location of
MEN1, has also been observed in 5–50% of sporadic endocrine tu-
mors, thus implicating the MEN1 gene in the etiology of these tu-
mors (Thakker et al., 1993). Approximatley 200 somatic MEN1
mutations (Fig. 4) have been reported between 1997 and 2007,
and these have occurred in several different endocrine tumors (Le-
mos and Thakker, 2008). Thus, these have been detected in 18% of
sporadic parathyroid tumors (total number, n = 452), 38% of gastri-
nomas (n = 105) (Wang et al., 1998), 14% of insulinomas (n = 43),
57% of VIPomas (n = 7) (Wang et al., 1998), 16% of non-functioning
pancreatic tumors (n = 32), 60% of glucagonomas (n = 5), 2.0% of
adrenal cortical tumors (n = 83) (Lemos and Thakker, 2008), 35%
of bronchial carcinoid tumors (n = 26) (Lemos and Thakker,
2008), 3.5% of anterior pituitary adenomas (n = 167) (Lemos and
Thakker, 2008; Prezant et al., 1998), 10% of angiofibromas
(n = 19), and 28% of lipomas (n = 8). These somatic mutations are
scattered throughout the 1830-bp coding region (Fig. 3), and 18%
are nonsense mutations, 40% are frameshift deletions or insertions,
6% are in-frame deletions or insertions, 7% are splice-site muta-
tions, and 29% are missense mutations (Fig. 4) (Lemos and Thakker,
2008). A comparison of the locations of the somatic and germ-line
mutations revealed a higher frequency (39% [somatic] vs. 23%
[germline]; P < 0.001) of somatic mutations in exon 2, but the sig-
nificance of this observation (Lemos and Thakker, 2008) in the con-
text of the Knudson two-hit hypothesis remains to be elucidated.
The tumors harboring a somatic MEN1 mutation had chromosome
11q13 LOH as the other genetic abnormality, or ‘‘hit’’, consistent
with Knudson’s hypothesis. These studies (Lemos and Thakker,
2008; Prezant et al., 1998; Wang et al., 1998) indicate that
although inactivation of the MEN1 gene may have a role in the eti-
ology of some sporadic endocrine tumors, the involvement of other
genes, for example, the GNAS1 gene encoding the G protein-stim-
ulatory a subunit (Lyons et al., 1990), with major roles in the eti-
ology of such sporadic endocrine tumors, is highly likely.
2.5. MEN1 mutations in hereditary endocrine disorders
The role of the MEN1 gene in the etiology of other inherited
endocrine disorders, in which either parathyroid or pituitary tu-
mors occur as an isolated endocrinopathy, has been investigated
by mutational analysis. MEN1 mutations have been reported in
42 families with isolated hyperparathyroidism (FIHP) (Hannan
et al., 2008; Lemos and Thakker, 2008), and 38% of these are
Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
7
missense mutations, and fewer than 31% are nonsense or frame-
shift mutations, which would result in a truncated and likely inac-
tivated protein. This contrasts significantly (P < 0.01) with the sit-
uation in MEN1 patients in whom more than 65% of the germ-
line mutations are protein-truncation and about 23% are missense
mutations (Fig. 4). These observations are consistent with a more
likely association between missense mutations and the milder
FIHP variant, but it is important to note that the mutations associ-
ated with FIHP are also scattered throughout the coding region and
not clustered, a situation that is similar to that found for germ-line
MEN1 mutations (Fig. 3). Furthermore, the occurrence of protein-
truncating mutations in FIHP patients and particularly deletions,
such as the 4 bp, involving codons 83–84 (Table 2), which are iden-
tical to those observed in MEN1 patients, makes it difficult to
establish an unequivocal phenotype–genotype correlation. How-
ever, the sole occurrence of parathyroid tumors in these families
that harbor MEN1 mutations that are similar to those found in fam-
ilies with MEN1 is remarkable, and the mechanisms that deter-
mine the altered phenotypic expressions of these mutations
remain to be elucidated. However, nonsense mutations (Tyr312-
Stop and Arg460Stop) have been detected (Olufemi et al., 1998)
in MEN1 families with the Burin or prolactinoma variant (Agarwal
et al., 1997) which is characterized by a high occurrence of prolac-
tinomas and a low occurrence of gastrinomas (Hao et al., 2004;
Olufemi et al., 1998). Furthermore, a splice mutation (c.446-
3c ? g) has been detected in an MEN1 kindred from Tasmania, in
whom there was an absence of somatotrophinomas (Burgess
et al., 2000). However, some other families with isolated acromeg-
aly do not have abnormalities of the MEN1 gene (Lemos and Thak-
ker, 2008), even though segregation analysis in families with
isloated acromegaly and LOH studies of somatotrophinomas indi-
cated that the gene was likely to be located on chromosome
11q13 (Soares et al., 2005). Interestingly, mutations of the aryl
hydrocarbon receptor interacting protein (AIP) gene, which is also
located on chromosome 11q13 and 2.7 Mb telomeric to the MEN1
gene, have been identified in some families with isolated acromeg-
aly (Vierimaa et al., 2006). However AIP mutations have not been
deteced in patients with MEN1, who do not have MEN1 mutations.
2.6. Genetic testing and screening in MEN1
MEN1 is an uncommon disorder, but because of its autosomal-
dominant inheritance, the finding of MEN1 in a patient has impor-
tant implications for other family members; first-degree relatives
have about a 50% risk of development of the disease (Trump
et al., 1996). Screening for MEN1 in patients involves the detection
of tumors and ascertainment of the germ-line genetic state, that is,
normal or mutant gene carrier (Fig. 1) (Thakker et al., 2012). Detec-
tion of tumors entails clinical, biochemical, and radiologic investi-
gations for MEN1-associated tumors in patients (Trump et al.,
1996). The characterization of the MEN1 gene (Chandrasekharappa
et al., 1997; The European Consortium on MEN1, 1997) has facili-
tated identification of individuals who have mutations and hence
a high risk of acquiring the disease (Figs. 2 and 3).
2.6.1. MEN1 mutational analysis
MEN1 mutational analysis is helpful in clinical practice in sev-
eral ways that include: (1) confirmation of the clinical diagnosis;
(2) identification of family members who harbor the MEN1 muta-
tion and require screening for tumor detection and early treat-
ment; and (3) identification of the 50% of family members who
do not habour the familial germline MEN1 mutation and can there-
fore be reassured and alleviated of the burden of anxiety of devel-
oping tumors. This latter aspect cannot be over-emphasized as it
not only helps to reduce the personal cost to the individuals and
their children, but also to the health services in not having to
8 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

Table 5
Summary of biochemical and radiological screening guidelines in individuals at high risk of developing MEN1.

Tumor Age to begin (yr) Biochemical test (annually) Imaging test (every 3 years)
Parathyroid 8 Calcium, PTH None
Pancreatic neuroendocrine
Gastrinoma 20 Gastrin (±gastric acid output) None
Insulinoma 5 Fasting glucose, insulin None
Other enteropancreatic <10 Chromogranin-A; pancreatic polypeptide, glucagon; VIP MRI, CT or EUS (annually)
Anterior pituitary 5 Prolactin, IGF-1 MRI (every 3 years)
Adrenal <10 None, unless symptoms or signs of functioning tumor MRI or CT annually with pancreatic imaging
and/or tumor >1 cm are identified
Foregut carcinoid 20 None CT or MRI (every 1–2 years)

CT, computer tomography; MRI, magnetic resonance imaging; EUS, endoscopic ultrasound.
Reproduced from Thakker RV: Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab 97: 2990–3011, Ó2012. The Endocrine
Society (Thakker et al., 2012).

undertake unnecessary biochemical and radiological investigations
(Table 5). Thus, MEN1 mutational analysis can be useful in clinical
practice.
The current guidelines recommend that MEN1 mutational anal-
ysis should be undertaken in: (1) an index case with two or more
MEN1-associated endocrine tumors (i.e. parathyroid, pancreatic
or pituitary tumors); (2) asymptomatic first degree relatives of a
known MEN1 mutation carrier; (3) a first-degree relative of a
MEN1 mutation carrier expressing familial MEN1 (i.e. having
symptoms, signs, biochemical or radiological evidence for one or
more MEN1-associated tumors) (Thakker et al., 2012). In addition,
MEN1 mutational analysis should be considered in patients with
suspicious or atypical MEN1. This would include individuals with:
parathyroid adenomas before the age of 30 years or multigland
parathyroid disease; gastrinoma or multiple pancreatic islet cell
tumors at any age; or individuals who have two or more MEN1-
associated tumors, which are not part of the classical triad of para-
thyroid, pancreatic islet and anterior pituitary tumors (e.g. para-
thyroid tumor plus adrenal tumor) (Thakker et al., 2012).
Family members, including asymptomatic individuals who have
been identified to harbor a MEN1 mutation will require biochemi-
cal and radiological screening (5). In contrast, those relatives who
do not harbor the MEN1 mutation will have their risk of developing
MEN1-associated endocrine tumors markedly decreased from 1 in
2 for an autosomal dominant disorder, to 1 in 3000, 1 in 100,000
and 1 in 1000 which are the respective risks for parathyroid, pan-
creatic islet cell and anterior pituitary tumors for the general pop-
ulation; thus, these relatives without the MEN1 mutation will be
freed from the requirement of further repeated clinical investiga-
tions (Lemos and Thakker, 2008; Thakker et al., 2012).
MEN1 germline mutational analysis should be considered in
those presenting at an early age with a single, apparently sporadic
MEN1-associated tumor. The occurrence of germline MEN1 muta-
tions in all patients with sporadic, non-familial parathyroid adeno-
mas is 1%, in gastrinomas is 5%, in prolactinoma is 1%, and in
foregut carcinoids is 2% (Thakker et al., 2012). However, the occur-
rence of MEN1 mutations tumors in patients developing parathy-
roid tumors below the age of 40 years has been reported to be
higher at 5–13%. The occurrence rates of germline MEN1 mutations
in individuals presenting with a single apparent sporadic pancre-
atic NET at similarly younger age, has not been established, and
the current guidelines recommend that MEN1 mutational analysis
should be considered in those with gastrinoma or multiple pancre-
atic NETS (Thakker et al., 2012).
Mutational analysis in asymptomatic individuals should be
undertaken at the earliest opportunity, and where possible in the
first decade of life as tumors have developed in some children by
the age of 5 years (Newey et al., 2009; Stratakis et al., 2000; Thak-
ker et al., 2012). Appropriate biochemical and radiological investi-
gations aimed at detecting the development of tumors should then
be undertaken in these individuals (Tables 1 and 5). The current
guidelines recommend that these investigations should commence
from the age of 5 years to detect anterior pituitary tumors and ins-
ulinomas, the age of 8 years to detect parathyroid tumors, and the
age of 20 years to detect gastrinomas and foregut carcinoid tumors
(Table 5), and be undertaken thereafter on an annual basis (Thak-
ker et al., 2012).
2.7. Detection of MEN1 tumors
Biochemical screening for the development of MEN1 tumors in
asymptomatic members (Fig. 2) of families with MEN1 is of great
importance in as much as earlier diagnosis and treatment of these
tumors may help reduce morbidity and mortality (Thakker et al.,
2012). The age-related penetrance (i.e., the proportion of gene car-
riers manifesting symptoms or signs of the disease by a given age)
has been ascertained (Bassett et al., 1998) (Fig. 5), and the muta-
tion appears to be nonpenetrant in those younger than 5 years.
Thereafter, the mutant MEN1 gene has a high penetrance, being
greater than 50% penetrant by 20 years of age and greater than
95% penetrant by 40 years (Bassett et al., 1998). Screening for
MEN1 tumors is difficult because the clinical and biochemical
manifestations in members of any one family are not uniformly
similar (Thakker et al., 1989; Trump et al., 1996). Attempts to
screen for the development of MEN1 tumors in the asymptomatic
relatives of an affected individual have depended largely on mea-
suring the serum con centrations of calcium, gastrointestinal (g–
i) hormones (e.g., gastrin), and prolactin, as well as on radiologic
imaging of the abdomen and pituitary (Thakker et al., 1989; Thak-
ker, 1998). Parathyroid overactivity causing hypercalcemia is al-
most invariably the first manifestation of the disorder and has
become a useful and easy biochemical screening investigation
(Trump et al., 1996). In addition, hyperprolactinemia, which may
be asymptomatic, may represent the first manifestation in fewer
than 10% of patients and may thus also be a useful and easy bio-
chemical screening investigation (Thakker et al., 2012; Trump
et al., 1996). Pancreatic involvement in asymptomatic individuals
has been detected by estimating the fasting plasma concentrations
of gastrin, PP, and glucagon and by abdominal imaging (Scarsbrook
et al., 2006; Thakker et al., 2012; Trump et al., 1996). However, one
study has shown that a stimulatory meal test is a better method for
detecting pancreatic disease in individuals who have no demon-
strable pancreatic tumors by CT. An exaggerated increase in serum
gastrin or PP or both proved to be a reliable early indicator for the
development of pancreatic tumors in these individuals.
At present, it is suggested that individuals at high risk for MEN1
(i.e., mutant gene carriers) undergo biochemical screening (Fig. 6)
at least once per annum and also have baseline pituitary and
abdominal imaging (e.g., MRI or CT), which should then be re-
peated at 1- to 3-year intervals (Table 5) (Thakker et al., 2012).
Screening should commence in early childhood because the
disease has developed in some individuals by the age of 5 years

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
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 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx
Fig. 5. Age distributions (A) and age-related penetrance (B) of multiple endocrine
neoplasia type 1 (MEN1) determined from an analysis of 174 mutant gene carriers.
A, The age distributions were determined for three groups of MEN1 mutant gene
carriers from 40 families in whom mutations were detected (Bassett et al., 1998).
The 91 members of group A had symptoms, whereas the 40 members of group B
were asymptomatic and detected by biochemical screening. The 43 members of
group C represent individuals who are MEN1 mutant gene carriers (see Fig. 2) and
who remain asymptomatic and biochemically normal. The ages included for
members of groups A, B, and C are those at the onset of symptoms, at the finding of
the biochemical abnormality, and at the last clinical and biochemical evaluation,
respectively. Groups B and C contained members who were significantly younger
than those in group A (P < 0.001). The younger age of the group C mutant gene
carriers is consistent with an age-related penetrance for MEN1, which was
calculated (B) for the first five decades. The age-related penetrance (i.e., the
proportion of mutant gene carriers with manifestations of the disease by a given
age) increased steadily from 7% in the group younger than 10 years to 52%, 87%,
98%, 99%, and 100% by the ages of 20, 30, 40, 50, and 60 years, respectively. The
residual risk (100% – age-related penetrance) for the development of MEN1 tumors
in asymptomatic mutant gene carriers who are biochemically normal would then
be 93%, 48%, 13%, 2%, and 1% at the ages of 10, 20, 30, 40, and 50 years, respectively.
(From Bassett JHD, Forbes SA, Pannett AAJ, et al.: Characterization of mutations in
patients with multiple endocrine neoplasia type 1 (MEN1). Am J Hum Genet 62:
232–244, 1998, with permission.) (Bassett et al., 1998).
(Thakker et al., 2012), and it should continue for life because the
disease has not developed in some individuals until the eighth
decade. The screening history and physical examination should
be directed toward eliciting the symptoms and signs of hypercalce-
mia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypo-
pituitarism, galactorrhea and amenorrhea in women, acromegaly,
Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
9
Cushing’s disease, and visual field loss and the presence of subcu-
taneous lipomas, angiofibromas, and collagenomas (Thakker et al.,
2012; Trump et al., 1996). Biochemical screening should include
estimations of serum calcium, PTH, gastrointestinal hormones
(e.g., gastrin, insulin with a fasting glucose, glucagon, VIP, and
PP), chromogranin A, prolactin, and IGF-1 in all individuals (Thak-
ker et al., 2012), and more specific endocrine-function tests should
be undertaken in individuals who have symptoms or signs sugges-
tive of a clinical syndrome. Radiologic screening should include an
MRI (or CT scanning) of the pancreas, adrenals, and pituitary, ini-
tially as a baseline and then every 1–3 years, as well as imaging
for foregut carcinoids (Scarsbrook et al., 2006; Thakker et al., 2012).
2.8. MEN1 phenocopies
Approximately 5–25% of patients with MEN1 may not have
mutations of the MEN1 gene. This variability in detecting MEN1
mutations may partly be attributable to differences in methods
used to identify the mutations; for example most studies do
not systematically examine for large gene deletions, which may
be found in up to 33% of patients who do not have coding region
mutations (Cavaco et al., 2002). In addition, this variability may
be due to phenotype ascertainment, as some studies have in-
cluded non-familial (i.e. sporadic) patients who may have devel-
oped only two (or fewer) endocrine tumors, and the detection
rate for MEN1 mutations in these patients was found to be
<5% (Tham et al., 2007). Such patients with MEN1-associated tu-
mors but without MEN1 mutations may represent phenocopies,
or have mutations involving other genes. Phenocopy refers to
the development of disease manifestations usually associated
with mutations of a particular gene, but instead are due to an-
other etiology, and the occurrence of phenocopies, has been re-
ported in 5–10% of MEN1 kindreds (Burgess et al., 2000;
Newey and Thakker, 2011; Turner et al., 2010). These phenocop-
ies occurred in two settings. Firstly, in the context of familial
MEN1 (Fig. 1), in which a patient with one MEN1-associated tu-
mor, e.g. a prolactinoma, did not have the familial mutation; and
secondly, in the context of clinical MEN1, in which patients with
two MEN1-associated tumors, who did not have an MEN1 muta-
tion, were demonstrated to have involvement of other genes.
These genes may include: CDC73, which encodes parafibromin,
whose mutations result in the Hyperparathyroid–jaw tumor
(HPT–JT) syndrome; the calcium sensing receptor (CaSR), whose
mutations result in familial benign hypercalciuric hypercalcemia
(FBHH) (Turner et al., 2010); and the aryl hydrocarbon receptor-
interacting protein (AIP), a tumor suppressor located on chromo-
some 11q13 whose mutations are associated with familial iso-
lated pituitary adenomas (FIPA) (Belar et al., 2012). The
occurrence of MEN1 phenocopies may confound the diagnosis
of MEN1 (Fig. 1) in an individual, and it therefore appears advis-
able to offer genetic testing to determine the MEN1 mutation
status to symptomatic family members within a MEN1 kindred,
as well as to all index cases (i.e. patient) with two or more
endocrine tumors. If a MEN1 mutation is not identified in the in-
dex case with two or more endocrine tumors, then clinical and
genetic tests for other disorders such as HPT–JT, FBHH, or FIPA
should be considered, as these patients may represent phenocop-
ies for MEN1.
3. Function of menin
Initial analysis of the predicted amino acid sequence of menin
did not reveal homologies to any other proteins, sequence motifs,
signal peptides, or consensus nuclear localization signal (Chandr-
asekharappa et al., 1997), and thus the putative function of menin
10 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

Fig. 6. An approach to screening in an asymptomatic relative of a patient with multiple endocrine neoplasia type 1 (MEN1). The relative should have first undergone clinical
evaluation for MEN1-associated tumors to establish that the individual is asymptomatic. Relatives who are symptomatic, who should also have a test for MEN1 mutations,
should proceed to appropriate investigations and management. If mutational analysis for MEN1 is not available, then this protocol could be adapted for first-degree relatives
(Trump et al., 1996). The use of mutational analysis and such screening methods in children is controversial and varies in different countries. It has been suggested that
nonessential genetic testing in a child who is not old enough to make important long-term decisions be deferred. However, the finding that a child from a family with MEN1
does not have any MEN1 mutations removes the burden of repeated clinical, biochemical, and radiologic investigations and enables health resources to be more effectively
directed toward those children who are MEN1 mutant gene carriers. The approaches to genetic testing and screening in MEN1 vary in different countries. PIT, pituitary; PANC,
pancreas; ADR, adrenal; CAR, carcinoid; PTH, parathyroid hormone; PRL, prolactin; IGF-1, insulin-growth-factor-1; CgA, chromogranin A; and g–i, and gastro-intestinal gut-
hormones. (Reproduced with permission from Thakker RV (2010) Multiple Endocrine Neoplasia Type 1. In Endocrinology, sixth ed., Eds: LJ De Groot, JL Jameson.) (Thakker,
2010).

could not be deduced. However, studies based on immunofluores-
cence, Western blotting of subcellular fractions, and epitope
tagging with enhanced green fluorescent protein revealed that me-
nin was located primarily in the nucleus (Guru et al., 1998). Menin
has been shown to have at least three nuclear localization signals
(NLSs) that are located in the C-terminal quarter of the protein
(Guru et al., 1998; La et al., 2006) (Fig. 3). Interestingly, the trun-
cated MEN1 proteins that would result from the nonsense and
frameshift mutations, if expressed, would lack at least one of these
nuclear localization signals (Fig. 3). Menin is predominantly a nu-
clear protein in non-dividing cells, but in dividing cells, it is found
in the cytoplasm (Guru et al., 1998). The function of menin still re-
mains to be elucidated, but it has been shown to interact with a
number of proteins that are involved in transcriptional regulation
(Agarwal et al., 1999; Dreijerink et al., 2006; Heppner et al.,
2001; Hughes et al., 2004; Karnik et al., 2005; La et al., 2007; Milne
et al., 2005; Roudaia and Speck, 2008; Scacheri et al., 2006; Yokoy-
ama and Cleary, 2008; Yokoyama et al., 2004), genome stability,
cell division and proliferation (Lemos and Thakker, 2008) (Fig. 3
and Table 6). Thus, in transcriptional regulation, menin has been
shown to interact with: the activating protein-1 (AP-1), transcrip-
tion factors JunD (Agarwal et al., 1999) and C-Jun (Yumita et al.,
2003), and to suppress Jun-mediated transcriptional activation;
members (e.g., p50, p52, and p65) of the NF-RB family of transcrip-
tional regulators to repress NF-RB-mediated transcriptional
activation (Heppner et al., 2001); members of the Smad family,
Smad3 and the Smad 1/5 complex, to inhibit the transforming
growth factor-b (TGF-b) and the bone morphogenetic protein-2
(BMP-2) signaling pathways, respectively; Runx2, also called cbfa1,
which is a common target of TGF-b and BMP-2 in differentiating
osteoblasts (Sowa et al., 2004); and the mouse placental embryonic
(pem) expression gene, which encodes a homeobox-containing
protein. Recently, the forkhead transcription factor CHES1 has been
shown to be a component of this transcriptional repressor complex
and to interact with menin in an S-phase checkpoint pathway re-
lated to DNA damage response. Menin uncouples ELK-1, JunD,
and c-Jun phosphorylation from mitogen-activated protein kinase
(MAPK) activation and suppresses insulin-induced c-Jun-mediated
transactivation in CHO-1R cells.
Menin has also been reported to directly bind to doubled-
stranded DNA and this is mediated by the positively charged resi-
dues in the nuclear localization signals (NLSs) in the carboxyl ter-
minus of menin. The NLSs appear to be necessary for menin to
repress the expression of the insulin-like growth factor binding
protein-2 (IGFBP-2) gene by binding to the IGFBP-2 promoter. In
addition, each of the NLSs has also been reported to be involved
in menin-mediated induction of caspase 8 expression (La et al.,
2006, 2007). The NLSs may therefore have roles in controlling gene
transcription as well as targeting menin into the nucleus. Further-
more, gene expression profile studies, using pituitary and

Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx
Table 6
Functions of menin indicated by direct interactions with proteins and other
molecules.
Functiona Interacting partner
Transcription JunD
regulation
NF-jB (P50, P52, P65)
pem
SIN3A
HDAC
Smad1
Smad3
Smad5
Runx2
MLL histone methyl-transferase complex
ER-Alpha
CHES1
Double-stranded DNA
Genome stability RPA2
FANCD2
Cell division NMMHC II-A
GFAP
Vimentin
Cell cycle control NM23 (A)
ASK
Epigenetic regulation MLL histone methyl-transferase complex ER-Alpha
HDAC
a
Functions reported include involvement in cell cycle withdrawal, decrease of
cell motility, cell differentiation, apoptosis and DNA repair. (Adapted from Lemos M
and Thakker RV: Multiple Endocrine Neoplasia Type 1 (MEN1): Analysis of 1336
Mutations Reported in the First Decade Following Identification of the Gene. Human
Mutation 29: 22–32, 2008, with permission) (Lemos and Thakker, 2008).
pancreatic islet tumors obtained from men1 mouse models, have
revealed altered expression of genes involved in transcription, cell
cycle and chromatin remodeling.
A role for menin in controlling genome stability has been pro-
posed because of its interactions with: a subunit of replication pro-
tein (RPA2), which is a heterotrimeric protein required for DNA
replication, recombination, and repair; and the FANCD2 protein,
that is involved in DNA repair and mutations of which result in
the inherited cancer-prone syndrome of Fanconi’s anemia. Menin
also has a role in regulating cell division as it interacts with the
nonmuscle myosin II-A heavy chain (NMHC II-A), which partici-
pates in mediating alterations in cytokinesis and cell shape during
cell division and the glial fibrillary acidic protein (GFAP) and
vimentin, which is involved in the intermediate filament network.
Menin also has a role in cell cycle control as it interacts with: the
tumor metastases suppressor NM23H1/nucleoside diphosphate ki-
nase, which induces guanosine triphosphate (GTP)ase activity; and
the activator of S-phase kinase (ASK), which is a component of the
Cdc7/ASK kinase complex that is crucial for cell proliferation. In-
deed, menin has been shown to completely repress ASK-induced
cell proliferation (Schnepp et al., 2004).
The functional role of menin as a tumor suppressor also has
been investigated, and studies in human fibroblasts have revealed
that menin acts as a repressor of telomerase activity via hTERT (a
protein component of telomerase) (Lin and Elledge, 2003). Further-
more, overexpression of menin in the human endocrine pancreatic
tumor cell line (BONI) resulted in an inhibition of cell growth (Stal-
berg et al., 2004) that was accompanied by upregulation of JunD
expression but downregulation of d-like protein 1/preadipocyte
factor-1, proliferating cell nuclear antigen, and QM/Jif-1, which is
a negative regulator of C-Jun (Stalberg et al., 2004). These findings
of growth suppression by menin also are observed in other cell
types. Thus, expression of menin in RAS-transformed NIH3T3 cells
partially suppressed the RAS-mediated tumor phenotype in vitro
and in vivo (Stalberg et al., 2004), and overexpression of menin
Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
11
in CHO-IR cells also suppressed insulin-induced AP-1 transactiva-
tion, and this was accompanied by an inhibition of C-Fos induction
at the transcriptional level (Kim et al., 1999). Furthermore, menin
expression in Men1-deficient mouse Leydig tumor cell lines in-
duced cell cycle arrest and apoptosis (Hussein et al., 2007). In con-
trast, depletion of menin in human fibroblasts resulted in their
immortalisation (Lin and Elledge, 2003). Thus, menin appears to
have a large number of functions through interactions with pro-
teins, and these mediate alterations in cell proliferation.
3.1. Menin and epigenetic regulation
Menin which acts as a scaffold protein, may increase or de-
crease gene expression by epigenetic regulation of gene expression
via histone methylation or acetylation. For examaple, menin has
been shown to be an integral component of histone methyltrans-
ferase complexes that contain members from the mixed-lineage
leukemia (MLL) and trithorax protein family (Hughes et al.,
2004). These can methylate the lysine 4 residue of histone H3
(H3K4) and H3K4 trimethylation is linked to activation of tran-
scription. Menin, by serving as a molecular adaptor, physically
links the MLL histone methyl transferase with the lens epithe-
lium-derived growth factor (LEDGF), which is a chromatin-associ-
ated protein implicated in the eitology of leukemia, autoimmunity
and human immuno-defeciency virus-1 (HIV-1) disease (Roudaia
and Speck, 2008; Yokoyama and Cleary, 2008). Thus, menin has a
critical function in the MLL complex and its regulation of multiple
transcriptional pathways, for example, menin, as a component of
this MLL complex, regulates the expression of genes such as the
Hox homeobox genes (Agarwal and Jothi, 2012; Yokoyama et al.,
2004) and the genes for cyclin-dependent kinase inhibitors, p27
and p18 (Karnik et al., 2005; Milne et al., 2005). Interestingly, spe-
cific deregulation of a subset of 23 Hox genes has been reported in
parathyroid tumors from patients with MEN1 (Shen et al., 2008). In
addition, menin has been shown to directly interact with protein
arginine methyltransferase 5 (PRMT5), and to recruit PRMT5 to
the promoter of the gene encoding the growth arrest-specific pro-
tein 1 (GAS1), which is an important factor for binidng of Sonic
Hedgehog (Shh) ligand to its cell surface receptor patched (PTCH1)
with subsequent activation of the Hedgehog signaling pathway,
which increases repressive histone arginine symmetric dimethyla-
tion (H4R3M2S) and suppresses GAS1 expression (Gurung et al.,
2013). GAS1 blocks entry to S phase and prevents cycling of normal
and transformed cells, hereby acting as a tumor suppressor. Fur-
thermore, menin has been reported to interact with the suppressor
of varigation 3–9 homolog family protein (SUV39H1) to mediate
H3K mehylation, and thereby silence transcrpitional activty of tar-
get genes (Yang et al., 2013). Menin has been shown to directly
interact with the nuclear receptor for estrogen (ERa) and to act
as a coactivator for ERa–mediated transcription, linking the acti-
vated estrogen receptor to histone H3K4 trimethylation (Dreijerink
et al., 2006). Additional studies have also shown that the interac-
tion of menin with JunD may be mediated by a histone deacetyl-
ase-dependent mechanism, via recruitment of an mSin3A-histone
deacetylase (HDAC) complex to repress JunD transcriptional activ-
ity (Kim et al., 2003, 2005). Thus, these studies reveal that menin
can act both as an activator and repressor of transcription by epi-
genetic mechanisms that involve integration of different chroma-
tin modification complexes. For example, menin may mediate
repression of genes targeted by the transcription factor JunD
through the mSin3A-histone deacetylse (HDAC) complex, and the
growth factor pleiotrophin gene through polycomb group com-
plex-mediated histone H3K27 methylation (Gao et al., 2009). Me-
nin may also promote expression of genes, such as those
encoding the cyclase-dependent-kinase (CDK) inhibitors, p27Kip1
and P18INK4c, via interaction with the MLL-HMT complex that
12 R.V. Thakker / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx
Fig. 7. Role of menin in regulating transcription by epigenetic mechanisms. Menin may act as an activator or repressor of transcription depending on its inteaction with the
MLL complex, HDAC or SUV39H1. Thus, interaction with MLL results in methylation of histone H3 (H3K4), which in turn regulates suppression of the CDK inhibitors p18 and
p27, and Hox genes, to suppress cell proliferation. However, interaction with HDAC and SUV39H1 results in acetylation of H3 and methylation of H3K9me3, respectively,
which in turn regulate expression of GBX2 and IGFBP2 to promote cell proliferation. Thus, menin plays a role in selective mediation of chromatin remodeling and thereby in
regulating gene expression and cell proliferation.
mediates histone H3K4 methylation (Fig. 7) (Huang et al., 2012;
Hughes et al., 2004; Karnik et al., 2005; Milne et al., 2005). Target-
ing of these epigenetic mechanisms by use of small molecules is
providing important insights for the development of therapeutic
compounds. For example, the crystal structures of human menin
in its free form and in complexes with MLL1 have shown that me-
nin contains a deep pocket that binds to a short peptide of MLL1
(Huang et al., 2012). High-throughput screening studies to identify
compounds that target menin and suppress its interaction with
MLL have identified that thienopyrimidine has such functions
(Grembecka et al., 2012; McCarthy, 2012; Shi et al., 2012). Further-
more, their structure activity analyses led to generation of some
thienopyrimidine analogs, which bind to wild-type menin but
not menin mutants that involve the interaction site with MLL,
and others which are capable of inhibiting the MLL-fusion pro-
tein-mediated leukemogenic transformation (Grembecka et al.,
2012; McCarthy, 2012; Shi et al., 2012). Thus, understanding the
role of menin in epigenetic mechanisms has provided a rational
and molecular basis for the development of menin-MLL inhibitors.
4. Multiple endocrine neoplasia type 4 (MEN4)
Approximately 5–10% of patients with MEN1 do not have muta-
tions of the MEN1 gene (Lemos and Thakker, 2008; Thakker et al.,
2012), and these patients may have mutations involving other
genes. One of these genes is the CDNK1B, which encodes the 196
amino acid cyclin-dependent kinase inhibitor (CK1) p27kip1 and
was identified to be involved by investigations of a recessive
MEN-like syndrome in a naturally occuring rat model, referred to
as MENX (Pellegata et al., 2006). Rats with MENX were observed
to develop parathyroid adenomas, pancreatic islet-cell hyperplasia,
thyroid C-cell hyperplasia, bilateral phaeochromocytomas, para-
gangliomas and cataracts. The disorder was inherited as an autoso-
mal recessive trait. Genetic mapping studies localized MENX to the
distal part of rat chromosome 4, a region that also contained the
putative tumor suppressor CK1P27kip1, which is also refered to
as p27. Mutational analysis of the CDNK1B gene identified, in rats
with MENX, a homozygous frameshifting insertion of 8 bp, at co-
don 177, that resulted in a missense peptide and termination at co-
don 218 (Pellegata et al., 2006). This CDNK1B mutation resulted in
an absence of p27 protein in the tumor cells (Pellegata et al., 2006).
These findings prompted studies in patients with MEN1, who did
not harbor MEN1 mutations, for abnormalities of CDKN1B which
in man is located on chromosome 12p13. This revealed that
Please cite this article in press as: Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology
(2013), http://dx.doi.org/10.1016/j.mce.2013.08.002
approximatley 3% of these patients with MEN1-associated tumors,
such as parathyroid adenomas, pituitary adenomas and pancreatic
NETs in association with gonadal, adrenal, renal and thyroid tu-
mors have CDNK1B mutations. To date, 8 different heterozygous
loss-of-function CDNK1B mutations have been identified in pa-
tients with MEN1-like tumors, and this indicates that MEN4 in
man is an autosomal dominant-disorder, unlike MENX in rats
which is autosomal recessive. In addition, germline CDNK1B muta-
tions may also, rarely, be found in patients with sporadic (i.e. non-
familial) forms of primary hyperparathyroidism.
5. Conclusions
Combined clinical and laboratory investigations of MEN1 have
resulted in an increased understanding of this disorder, which
may be inherited as an autosomal-dominant condition. Defining
the features of each disease manifestation in MEN1 has improved
patient management and treatment and has also facilitated a
screening protocol to be instituted. Application of the techniques
of molecular biology has enabled identification of the gene causing
MEN1 and detection of mutations in patients. In addition, these re-
cent advances have facilitated the identification of mutant MEN1
gene carriers who are at high risk for development of this disorder
and thus require regular and biochemical and radiologic screening
to detect the development of endocrine tumors. The function of the
protein encoded by the MEN1 gene, menin, has been shown to in-
volve regulation of transcription, which involves genetic mecha-
nisms, genome stability, and cell division, but much still remains
to be elucidated. Furthermore, inhibitors of the menin-MLL inter-
action hold promise for provoking new treatments.
Acknowledgments
I am grateful to the Medical Research Council (UK) for support;
and to Mrs. Tracey Walker for typing the manuscript.
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