Alternative titles; symbols
HGNC Approved Gene Symbol: MEN1
SNOMEDCT: 254627002, 30664006, 786037006; ICD10CM: E31.21; ICD9CM: 258.01;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,803,516-64,811,294 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Adrenal adenoma, somatic | 3 | ||
| Angiofibroma, somatic | 3 | |||
| Carcinoid tumor of lung | 3 | |||
| Lipoma, somatic | 3 | |||
| Multiple endocrine neoplasia 1 | 131100 | Autosomal dominant | 3 | |
| Parathyroid adenoma, somatic | 3 |
The MEN1 gene encodes menin, a nuclear scaffold protein that regulates gene transcription by coordinating chromatin remodeling. Menin interacts with several transcription factors, including JUND (165162), NFKB (164011), and SMAD3 (603109). MEN1 is considered to act as a tumor suppressor gene (summary by Canaff et al., 2012).
Chandrasekharappa et al. (1997) identified several candidate genes within the multiple endocrine neoplasia type I (MEN1; 131100) minimal interval on chromosome 11q13. One of the genes (MEN1) was found to encode a deduced 610-amino acid protein, which the authors designated menin. Northern blot analysis revealed ubiquitous expression of a 2.8-kb MEN1 transcript.
To identify additional candidate genes in the segment of less than 300 kb where the MEN1 locus is situated, Lemmens et al. (1997) used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes they identified, which they called SCG2 (suppressor candidate gene-2), proved to be identical to the MEN1 gene reported by Chandrasekharappa et al. (1997). The SCG2 transcript was 2.9 kb in all tissues studied, with an additional 4.2-kb transcript also being present in the pancreas and thymus. A human SCG2 cDNA clone, covering 2.3 kb at the 3-prime end of the gene, was isolated by hybridization screening. Northern blot analysis with this human sequence gave results identical to those from the bovine sequence.
Chandrasekharappa et al. (1997) determined that the MEN1 gene contains 10 exons.
Chandrasekharappa et al. (1997) identified the MEN1 gene on chromosome 11q13.
Based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein, Guru et al. (1998) demonstrated that menin is located primarily in the nucleus. They identified at least 2 independent nuclear localizations signals (NLSs), both located in the C-terminal fourth of the protein. They pointed out that among the 68 then-known independent disease-associated mutations, none of the 22 missense and 3 in-frame deletions affected either of the putative NLS sequences. However, if expressed, none of the truncated menin proteins resulting from the 43 known frameshift/nonsense mutations would retain both the NLSs.
Using a yeast 2-hybrid screen with menin as the bait, Agarwal et al. (1999) identified the transcription factor JunD (165162) as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin-JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that the tumor suppressor function of menin involves direct binding to JunD and inhibition of JunD-activated transcription.
Kaji et al. (2001) showed that menin inactivation by antisense RNA antagonizes transforming growth factor-beta (TGFB; 190180)-mediated cell growth inhibition. Menin interacts with SMAD3 (603109), and antisense menin suppresses TGFB-induced and SMAD3-induced transcriptional activity by inhibiting SMAD3/4-DNA binding at specific transcriptional regulatory sites. These results implicated a mechanism of tumorigenesis by menin inactivation.
To investigate how menin expression is regulated in both man and mouse, Zablewska et al. (2003) assayed a greater than 1 kb region upstream of the second exon of the MEN1 gene for promoter activity in luciferase reporter vectors. The basic promoter was located closely upstream of the most commonly expressed first exon. The region further upstream modified the activity. Repetitive elements of the short interspersed/Alu type covered the entire human upstream regulatory region and were the only apparent motif in common with its murine ortholog. They found that overexpression of menin in an inducible cell culture system downregulated the proximal promoter. In response to downregulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. They concluded that their data confirmed that the expression of the MEN1 gene is regulated by feedback from its product menin.
To explore telomerase regulation, Lin and Elledge (2003) employed a general genetic screen in HeLa cells to identify negative regulators of TERT (187270). They discovered 3 tumor suppressor/oncogene pathways involved in TERT repression, including menin, which is a direct repressor of TERT. Depleting menin immortalized primary human fibroblasts and caused a transformation phenotype when coupled with expression of simian virus 40 large and small T antigen and oncogenic RAS (190020).
Human ML-2 leukemia cells lack a normal MLL (159555) gene and exclusively express an MLL/AF6 (MLLT4; 159559) fusion protein. Yokoyama et al. (2005) showed that MLL/AF6 associated with menin (MEN1) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (142950), HOXA9 (142956), and HOXA10 (142957) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; 159556) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N-terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts.
Crystal Structure
Huang et al. (2012) reported the crystal structures of human menin in its free form and in complexes with MLL1 (159555) or with JUND (165162), or with an MLL1-LEDGF (603620) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.
Multiple Endocrine Neoplasia Type I
Chandrasekharappa et al. (1997) identified mutations in the MEN1 gene (613733.0001-613733.0012) in 14 probands from 15 families with multiple endocrine neoplasia type I. Twelve different heterozygous mutations were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism.
By mutation analysis of the SCG2 in 10 unrelated families with multiple endocrine neoplasia type I, Lemmens et al. (1997) identified 1 polymorphism and 9 different heterozygous mutations (1 missense, 4 nonsense, 1 insertional, and 3 deletional frameshifts) that segregated with the disease, thus providing confirmation for the identification of the MEN1 gene.
Giraud et al. (1998) studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families.
Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (613733.0032) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed.
In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype.
The observation of loss of heterozygosity involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis.
By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, Wautot et al. (2002) identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype.
Turner et al. (2002) ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516 (613733.0028) accounts for 36.6% of all mutations.
In 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs.
Park et al. (2003) investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma.
Familial Isolated Primary Hyperparathyroidism, MEN1 Variant
In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism, Teh et al. (1998) found that affected members had a germline missense mutation in the MEN1 gene (613733.0020). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (131100). The pattern of transmission was autosomal dominant with high penetrance, as in MEN1. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model.
In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas, Fujimori et al. (1998) identified a missense mutation in the MEN1 gene (613733.0021).
Somatic Mutations in the MEN1 Gene
Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (613733.0013) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). Heppner et al. (1997) suggested that many of these tumors likewise may have MEN1 somatic mutations.
Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (168450) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism.
Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors.
Prezant et al. (1998) screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis.
Heppner et al. (1999) studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH.
To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient.
To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, Kjellman et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity (LOH). The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (160980) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.
Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13.
Tahara et al. (2000) analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, 608455; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.
Sato et al. (2001) reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland.
Jiao et al. (2011) explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, 603186) and ATRX (300032). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. Jiao et al. (2011) also found mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors.
To examine the role of MEN1 in tumor formation, Crabtree et al. (2001) generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene.
Busygina et al. (2004) generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; 603473), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Busygina et al. (2004) concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (113705) and MSH2 (609309) genes.
To examine the potential role of Men1 in hematopoiesis, Chen et al. (2006) targeted Men1 excision in a temporally-controlled manner. Disruption of Men1 in mice after birth gradually led to decreased total white blood cell count but did not significantly reduce red blood cell numbers. There was also reduced Hoxa9 (142956) expression and reduced colony formation by hematopoietic progenitors. Chen et al. (2006) determined that Men1 directly activated Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitated the methylation of histone H3 on lysine-4 (H3K4), and recruited the methylated H3K4-binding protein Chd1 (602118) to the locus.
In addition to cancer risk, MEN1 patients have been reported to have neurologic symptoms, including depression (MDD; 608516) (Aoki et al., 1997). Leng et al. (2018) studied a mouse model of MEN1 loss of function and demonstrated that menin deficiency increased Nfkb (164011)-induced Il1b (147720) levels in astroglia of male mice subjected to mild stress and lipopolysaccharide (LPS) injections. Whereas germline knockout mice died shortly after birth, a brain-specific knockout for Men1 was viable, had reduced Men1 astroglial expression, and showed depressive-like behaviors such as reduced mobility and impaired sociability. When animals were treated with an Nfkb inhibitor or an Il1b receptor antagonist, the depressive phenotype was rescued. Leng et al. (2018) also genotyped a human cohort of 1,032 MDD patients and identified one SNP (rs375804228) with an odds ratio of 3.2. Transfection studies of this variant, a G503D substitution in exon 10, in HEK293T cells showed reduced p65 (RELA; 164014) DNA binding. Leng et al. (2018) concluded that astroglial menin deficiency or mutation is able to produce neuroinflammation contributing to MDD.
In a proband with multiple endocrine neoplasia type I (MEN1; 131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, changing residue 22 from leucine to arginine (L22R).
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of 4 bp starting from nucleotide 357 in the MEN1 gene.
In probands from 2 families with MEN1 (131100) not known to be related, Chandrasekharappa et al. (1997) identified a heterozygous 1-bp deletion of nucleotide 416, a cytidine, in the MEN1 gene.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of lys119.
In 2 probands with MEN1 (131100) from families not known to be related, Chandrasekharappa et al. (1997) identified a heterozygous deletion of nucleotide 512, a cytidine, in the MEN1 gene.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, converting codon 198 from tryptophan to stop.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of 4 bp in the MEN1 gene, starting from nucleotide position 735.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous deletion of nucleotide 1132, a guanine, in the MEN1 gene.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous 3-bp deletion in the MEN1 gene, resulting in deletion of glu363.
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous missense mutation in the MEN1 gene, converting codon 436 from tryptophan to arginine (W436R).
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation in the MEN1 gene, converting codon 436 from tryptophan to stop (W436X).
In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation at codon 527 of the MEN1 gene, converting arginine to stop (R527X).
Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 1 in 2,000. Heppner et al. (1997) stated that in more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as MEN1. In most cases, however, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal. Approximately 30% of sporadic parathyroid tumors show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumor suppressor gene. Among 33 sporadic parathyroid tumors (see 131100), Heppner et al. (1997) found a somatic MEN1 gene mutation in 7 (21%), while the corresponding MEN1 germline sequence was normal in each patient. All tumors with MEN1 gene mutations showed LOH on 11q13, making the tumor cells hemi- or homozygous for the mutant allele. They concluded that somatic MEN1 gene mutations contribute to tumorigenesis in a substantial number of parathyroid tumors not associated with the MEN1 syndrome, thus fulfilling the characteristics of the Knudson model. In 1 of the 7 cases with a somatic cell mutation, a GAG-to-AAG change was found in codon 26 (E26K).
In a sporadic case of MEN1 (131100), Agarwal et al. (1997) identified a heterozygous nonsense mutation in the MEN1 gene, converting glutamine-260 to stop (Q260X). The patient had multiple tumors of the parathyroid glands, Zollinger-Ellison syndrome, and growth hormone-prolactin macroadenoma of the anterior pituitary gland.
Lung carcinoids occur sporadically and rarely in association with MEN1 (see 131100). Debelenko et al. (1997) studied 11 sporadic lung carcinoids for LOH in 1 locus and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from an MEN1 patient was studied. In 4 of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All 4 tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1-bp insertion (1650insC) , a 1-bp deletion, a 13-bp deletion, and a single nucleotide substitution affecting a donor splice site. Each mutation predicted truncation or potentially complete loss of MEN1. The remaining 7 tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at 11q13 and a complex germline MEN1 gene mutation. The findings of this study represented the first defined genetic alteration in carcinoids.
Olufemi et al. (1998) demonstrated an arg460-to-ter mutation (R460X) in the MEN1 gene in affected members of 4 families with MEN1 (131100), originally described by Farid et al. (1980) and Bear et al. (1985). Affected members had prolactinomas, carcinoid tumors of the lung and thymus, and hyperparathyroidism. The disorder was called the MEN1 Burin variant by Bear et al. (1985). All 4 families lived in the Burin peninsula of Newfoundland. The ancestors of each of the 4 independently identified families came from a group of very small, isolated, now-abandoned communities within a 20-mile radius on the north shore of Fortune Bay. No single common ancestor was identified by examination of genealogic records, but there were common surnames in the earliest generations recorded. By haplotype analysis, Olufemi et al. (1998) demonstrated a common haplotype over a 2.5-Mb region that was shared by affected members of all 4 families.
In a case of sporadic lipoma (see 131100), Vortmeyer et al. (1998) identified deletion of TGTC from exon 2 of the MEN1 gene. The deletion was not found in constitutional DNA.
Angiofibromas are benign cutaneous tumors that can occur sporadically or as multiple lesions in association with inherited diseases. As a rule, multiple facial angiofibromas are thought to be specific for tuberous sclerosis (see 191100); however, Darling et al. (1997) showed that angiofibromas may also be associated with multiple endocrine neoplasia type I. Boni et al. (1998) investigated whether the MEN1 gene might be implicated in sporadic angiofibromas. For this purpose, they analyzed 19 sporadic facial angiofibromas (see 131100) for mutation in the MEN1 gene using PCR-based SSCP and sequencing analysis. All patients had a negative family history for tuberous sclerosis and MEN1 disease. Aberrant bands were detected in 2 tumors: one mutation was an A-to-T transversion at nucleotide 517 changing codon 135 from AAG (lys) to TAG (ile); the second mutation was a transversion of GG to AA at nucleotides 1184 and 1185 resulting in a change of codon 358 from GAG (glu) to GAA (also glu) and codon 359 from GAG (glu) to AAG (lys) (613733.0019). The mutations were in exons 2 and 8, respectively. The mutations were observed only in tumor DNA and not in normal control tissue. LOH analysis, performed using 2 polymorphic markers flanking the MEN1 gene, showed no LOH in any of the 19 angiofibromas, including the 2 displaying mutations.
See 613733.0018 and Boni et al. (1998).
In a Caucasian English family in which 7 family members from 2 generations had primary hyperparathyroidism, Teh et al. (1998) found that affected members had a germline missense mutation in codon 255 (GAG to AAG) of exon 4, causing an amino acid change from glutamic acid to lysine (glu255 to lys). The G-to-A transition at nucleotide 763 of the cDNA also gave rise to a HindIII restriction cleavage site for the mutant allele. This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1 (131100). The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model.
In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas (see MEN1, 131100), Fujimori et al. (1998) demonstrated a T-to-A transversion at codon 184 in exon 3, predicted to result in an amino acid change from valine to glutamic acid (V184E). (Fujimori et al. (1998) incorrectly described the nucleotide change as a transition and the amino acid change as valine to glutamine. The change was presumably GTG (val) to GAG (glu); this was confirmed by Fujimori (1999).)
Because loss of heterozygosity on 11q13 occurs in about 20% of sporadic adrenal neoplasms, and adrenal lesions, mostly benign, occur in up to 40% of patients from MEN1 kindreds, MEN1 was considered a prime candidate gene in these lesions. Schulte et al. (1999) studied 15 patients with sporadic adrenal adenoma (see 131100) and 1 patient with multinodular hyperplasia. Of the 16 patients, 4 had incidentally discovered masses ('incidentalomas'), 5 had Conn syndrome, 6 had Cushing syndrome (219080), and 9 had high sex hormone production. Schulte et al. (1999) performed direct DNA sequencing of the menin gene in 14 sporadic adrenal adenomas and 1 case of adrenal hyperplasia. They identified 1 heterozygous missense mutation, thr552 to ser, in a hormonally inactive adrenal adenoma. This is another example of mutation in the MEN1 gene causing a sporadic form of tumors that occur as part of MEN1 disease. Other examples include parathyroid adenoma, gastrinoma, and bronchial carcinoid tumors.
Stratakis et al. (2000) reported a 2.3-cm pituitary macroadenoma in a 5-year-old boy with familial MEN1 (131100). He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. Germline DNA of the propositus and his affected relatives had a heterozygous point mutation in the MEN1 gene that led to a his139-to-asp substitution. The patient had no other detectable germline mutations in either MEN1 allele. DNA sequencing and FISH with a MEN1 genomic DNA sequence probe each demonstrated 1 copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 'second hit' as a tumor cause. The authors stated that this patient represents the earliest presentation of any morbid endocrine tumor in MEN1.
In 7 unrelated families with MEN1 (131100), Turner et al. (2002) found a G-to-A transition at nucleotide 5168 in intron 4 of the MEN1 gene, which resulted in a novel acceptor splice site in intron 4. Use of this novel acceptor site leads to incorporation of the 7 bp 5-prime to the naturally occurring acceptor splice site, with resultant frameshift and premature termination.
In affected members of a family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a 3-bp in-frame deletion of GAA at codon 118-119 of the MEN1 gene. Turner et al. (2002) noted that this mutation had been reported in 8 other MEN1 families; this mutation had been recorded by Bassett et al. (1998).
In affected members of a family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a 4-bp deletion involving codons 209 to 211 in exon 3 of the MEN1 gene. The mutation was predicted to result in frameshift and premature termination after 11 amino acids.
In affected members of 2 families with MEN1 (131100), Turner et al. (2002) found a heterozygous G-to-A transition at nucleotide 7262 in exon 9 of the MEN1 gene, resulting in an asp418-to-asn (D418N) amino acid change.
In 1 family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a deletion of a C nucleotide at position 7773 in exon 10 of the MEN1 gene, resulting in a frameshift and premature termination 42 amino acids after codon 516.
In a woman with MEN1 (131100), Balogh et al. (2004) identified a heterozygous C-to-A transversion in exon 8 of the MEN1 gene, resulting in a cys354-to-ter (C354X) mutation. The woman was first investigated at the age of 25 years for abdominal discomfort and left upper abdominal pain. A giant pancreatic tumor was identified by abdominal ultrasonography and CT scan. The diagnosis of a clinically nonfunctioning pancreatic neuroendocrine tumor was established by clinical studies, and the patient underwent a distal pancreatectomy. Histology proved a well-differentiated multinodular neuroendocrine tumor of the pancreas. During surgery, a subcutaneous lipoma was removed from the abdominal wall. Two days later, the patient developed primary hyperparathyroidism, and 2 enlarged parathyroid glands were surgically removed. Her family history was unremarkable, except for an unknown disorder in her father that had caused an early death.
In 3 members of a Japanese family with MEN1 (131100) and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene, 878insCTGCAG (insertion of 6 nucleotides after nucleotide 878), resulting in the insertion of 2 amino acids, leu-gln, after amino acid 256 of the menin protein (256insLQ). The authors noted that CTGCAG is a palindromic sequence, repeated twice in the wildtype allele from nucleotides 879 to 890. Okamoto et al. (2002) found a significant difference (p = 0.0022) on chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas, and suggested that there may be a correlation between insulinoma development and mutations in exon 4 where JunD binding occurs.
In a Chilean family with familial isolated primary hyperparathyroidism (FIHP; 145000), Carrasco et al. (2004) identified a heterozygous G-to-A transition at nucleotide 7361 of the tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9+1G-A). All 11 family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and wildtype sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. The authors concluded that this mutation produces an aberrant splicing of mRNA that could lead to a truncated protein without activity, explaining the clinical picture of this patient and his family.
Among 19 Finnish MEN1 (131100) probands, Teh et al. (1998) identified a heterozygous 1466del12 mutation in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder.
Ebeling et al. (2004) used church records and MEN1 family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 and 1657insC (613733.0033). They traced the roots of 8 families with the 1466del12 mutation to a small village approximately 45 kilometers east of Oulu, where the founder couple were born in 1705 and 1709, respectively.
Ebeling et al. (2004) used church records and MEN1 (131100) family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC. Four families with the 1657incC mutation could be traced back to a couple living 200 kilometers northeast of Oulu born in 1844 and 1846, and not farther than only 4 generations from the youngest. The authors noted that while the most prevalent mutation (1466del12; 613733.0032) is a unique Finnish mutation, the 1657delC mutation seems to be a hotspot, as it has been found in 5 different MEN1 populations (Guo and Sawicki, 2001).
Frank-Raue et al. (2005) reported a family with coexistence of a mutation in the MEN1 gene, resulting in multiple endocrine neoplasia with recurrent hyperparathyroidism (131100) , and in the RET gene (Y791F; 164761.0034), which alone produced no clinical phenotype and carries a low risk of medullary thyroid carcinoma, also implicating a low incidence of pheochromocytoma and primary hyperparathyroidism. A heterozygous substitution of G to A at position +1 in intron 5 of the MEN1 gene disrupted the consensus sequence in the splice donor site. This was predicted to lead to a nonsense peptide sequence from this position and premature termination of protein synthesis. Two patients carrying both mutations had typical manifestations of MEN1; the third patient carrying both mutations, being 6 years of age at the time of the report, showed no clinical manifestations. The authors concluded that the 2 mutations do not interact.
In affected members of a 3-generation family with MEN1 (131100), Canaff et al. (2012) identified a heterozygous G-to-A transition in intron 3 of the MEN1 gene. Patient lymphoblastoid cells showed a wildtype transcript as well as an aberrant transcript with an in-frame deletion of 35 amino acids (184_218). In vitro studies and studies in patient cells showed that the mutant transcript was expressed and able to mediate the normal inhibition of the activity of some transcriptional regulators, including JunD (165162). However, it was defective in mediating TGF-beta (190180)-stimulated Smad3 (603109) tumor suppressor activity. Patient lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-beta than cells from an unaffected family member. Canaff et al. (2012) concluded that this mutant menin isoform causes loss of control of cell proliferation via the selective loss of the TGF-beta signaling pathway, contributing to the development of MEN1.
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