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

Abstract

Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (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 mutations 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.

Keywords: Histone methylation; Neuroendocrine tumors; Pancreatic islet; Parathyroid; Pituitary; Tumors.

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).

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).

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 5′ part of exon 2, and the 3′ 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.784−9G>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-κB) (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).

Fig. 4

Frequency of germ-line and somatic MEN1 mutations. A total of 1133 germ-line mutations and 203 somatic mutations have been reported (Agarwal et al., 1997), and these are of diverse types (e.g., nonsense, frameshifts, deletions, insertions, splice-site, and missense mutations). The frequencies of each type of mutation in the germ-line and somatic groups are similar, with the exception of the missense mutations, which are found more frequently in tumors (i.e., the somatic group). (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).

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).

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).

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.