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.
Mol Cell Endocrinol. 2014 Apr 5;386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. Epub 2013 Aug 8.
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.
多发性内分泌腺瘤病（MEN）的特征是在单个患者中发生涉及两个或更多内分泌腺体的肿瘤。已经认识到并称为四大主要形式的 MEN，它们是常染色体显性遗传疾病，分别为：MEN1 型（MEN1），由于 menin 突变引起；MEN2（以前称为 MEN2A），由于编码在转染过程中重排的酪氨酸激酶受体（RET）原癌基因的突变引起；MEN3（以前称为 MEN2B），由于 RET 突变引起；以及 MEN4，由于细胞周期蛋白依赖性激酶抑制剂（CDNK1B）突变引起。每种 MEN 类型都与特定肿瘤的发生有关。因此，MEN1 的特征是甲状旁腺、胰岛和垂体前叶肿瘤的发生；MEN2 的特征是与嗜铬细胞瘤和甲状旁腺肿瘤相关的甲状腺髓样癌（MTC）的发生；MEN3 的特征是 MTC 和嗜铬细胞瘤的发生与马凡氏体型、粘膜神经瘤、髓鞘角膜纤维和肠道自主神经节功能障碍相关，导致巨结肠；MEN4，也称为 MENX，其特征是甲状旁腺和垂体前叶肿瘤的发生，可能与肾上腺、肾脏和生殖器官的肿瘤有关。本综述将重点介绍 MEN1 和 MEN4 综合征的临床和分子细节。引起 MEN1 的基因位于 11q13 染色体上，编码一个 610 个氨基酸的蛋白质 menin，它在细胞分裂、基因组稳定性和转录调节中具有功能。menin 作为支架蛋白，可通过组蛋白甲基化对基因表达进行表观遗传调控，增加或减少基因表达。因此，menin 通过形成混合谱系白血病（MLL）复合物的亚单位，在赖氨酸 4（H3K4）处三甲基化组蛋白 H3，促进细胞周期蛋白依赖性激酶（CDK）抑制剂等靶基因的转录活性；并通过与抑色素 3-9 同源家族蛋白（SUV39H1）相互作用，介导 H3K 甲基化，从而沉默靶基因的转录活性。与 Knudson 的两次打击假说一致，MEN1 相关肿瘤携带种系和体细胞突变。识别具有种系 MEN1 突变的个体有助于对该高危人群进行适当的临床、生化和影像学筛查，然后可以考虑更早地实施治疗。MEN4 是由 CDNK1B 杂合突变引起的，CDNK1B 编码 196 个氨基酸的 CDK1 p27Kip1，其被 H3K4 甲基化激活。
