Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610–amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83–84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210–211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype–genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. Hum Mutat 29(1), 22–32, 2008. © 2007 Wiley-Liss, Inc.

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Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene

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

Multiple endocrine neoplasia type 1 (MEN1).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues. The three main endocrine tissues most frequently affected by tumors are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Tumors are caused by a heterozygous germline-inactivating mutation in the MEN1 gene (1st hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (2nd hit), leading to complete loss of function of the encoded protein menin. Most of the disease features and tumors are recapitulated in mouse models with heterozygous germline loss of the Men1 gene. Also, tissue-specific tumors are observed in mouse models with homozygous somatic loss of the Men1 gene specifically in MEN1-associated endocrine tissues. Hence, mouse models could serve as possible surrogates for studying MEN1 and related states. To gain insights into MEN1 pathophysiology, menin-interacting partners and pathways have been identified to investigate its tumor suppressor and other functions. Also, the 3D crystal structure of menin has been deciphered which could be useful to reveal the relevance of MEN1 gene mutations and menin's interactions. This chapter covers clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its product protein menin.

Multiple endocrine neoplasia type 1.

MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic α- and β-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse β-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in ∼30% of adaptive β-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early β-cell lesions and insulinomas that developed in β-cell specific Men1 mutant mice, appearing in >80% of β-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured βTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse β-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult β-cell proliferation and Men1-related tumorigenesis.

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse.

Reconstituted expression of menin in Men1-deficient mouse Leydig tumour cells induces cell cycle arrest and apoptosis

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Reconstituted expression of menin in Men1-deficient mouse Leydig tumour cells induces cell cycle arrest and apoptosis