MEN1 gene and its mutations: Basic and clinical implications

Abstract

Heterozygous germline mutations of the tumor-suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by pituitary, parathyroid, and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and related disorders. Neither mutation hot spot nor phenotype-genotype correlation has been established in MEN1 although some missense mutations may be specifically associated with a phenotype of familial isolated hyperparathyroidism. The gene product menin has been implicated in multiple roles, including gene transcription, maintenance of genomic integrity, and control of cell division and differentiation. These multiple functions are likely to be conferred by association with multiple protein factors. Occurrence of MEN1-causing missense mutations throughout menin also suggests the requirement of multiple binding factors for its full tumor-suppressive activity. The effect of menin depletion is highly tissue specific, but its underlying mechanism remains to be elucidated. A DNA test for MEN1 germline mutations is a useful tool for diagnosis of MEN1 although it needs further improvements. The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors. So far, MEN1 gene mutations have not been implicated in any other human diseases.The product of the MEN1 gene, menin, is a 610-amino acid protein that exhibits no apparent sequence similarity to any other known protein.(1) Thus, its biochemical function can not be deduced from its structure. In the last decade, a number of studies have demonstrated physical and functional associations between menin and diverse proteins of known function, shedding light on its molecular function. These menin-interacting proteins include nuclear proteins such as transcription factors, histone deacetylases, and histone methyltransferases, suggesting that menin is involved in gene transcription. Several lines of evidence also suggest that menin is involved in the maintenance of genomic integrity. Although menin is localized mainly to cell nuclei, possible extranuclear functions have not been excluded because various cytoplasmic proteins bind to menin.Although the molecular function of menin is still poorly understood, identification of the MEN1 gene has enabled a direct DNA test for predisposition to MEN1. In the present review, recent findings on the MEN1 gene are summarized and its mutations are discussed from basic and clinical points of view. Structure and expression of the MEN1 geneThe human MEN1 gene comprises 10 exons distributed over 7 kb in the chromosome region 11q13 and encodes mRNA of approximately 2.8 kb (Fig. 2).(1) Exons 2 through 10 encode th...

Expression and subcellular localization of menin in human cancer cells

“…Menin, encoded by the multiple endocrine neoplasia type I (MEN1) gene, is a nuclear protein which is mutated in patients with a dominantly inherited disorder characterized by the appearance of combinations of tumors in a number of endocrine tissues, including the pituitary and parathyroid glands and the pancreas (1,2), and occasionally in non-endocrine glands (3,4). The human MEN1 gene has been identified by positional cloning and is localized to chromosome 11q13.…”

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

“…(4) Diverse roles have been implicated for menin, including cell cycle control, cell differentiation and DNA repair, which are likely to be conferred by interaction with various menin-binding proteins. (2) Menin is considered to be a scaffold protein tethering such proteins to specific gene loci. (5) Although the mechanism of how menin is involved in gene regulation has been elucidated to some extent, the basis for tissue-specific tumorigenesis in MEN1 remains unknown.…”

A new double substitution mutation in the MEN1 gene: a limited penetrance and a specific phenotype

“…9 Primary hyperparathyroidism (pHPT) is the most frequent expression of MEN1 with a penetrance between 73 and 100% by age 50 years. 10,11 The penetrance of the pancreatic neuroendocrine tumours (pNETs) is very high, reaching between 65 and 85% at the age of 60. 11,12 The pNETs arising from pancreatic islet cells may be functioning, with production of hormones such as gastrin, insulin, vasoactive intestinal polypeptide (VIP), glucagon and somatostatin, or non-functioning with the release of pancreatic polypeptide (PP).…”

“…10,11 The penetrance of the pancreatic neuroendocrine tumours (pNETs) is very high, reaching between 65 and 85% at the age of 60. 11,12 The pNETs arising from pancreatic islet cells may be functioning, with production of hormones such as gastrin, insulin, vasoactive intestinal polypeptide (VIP), glucagon and somatostatin, or non-functioning with the release of pancreatic polypeptide (PP). 11 The prevalence of pituitary tumours (PITs) in MEN1 patients vary from 20 to 65%.…”