Karges W, Jostarndt K, Maier S, Flemming A, Weitz M, Wissmann A, Feldmann B, Dralle H, Wagner P, Boehm B O
Division of Endocrinology, Department of Internal Medicine, University of Ulm, Ulm, Germany.
J Endocrinol. 2000 Jul;166(1):1-9. doi: 10.1677/joe.0.1660001.
Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.
多发性内分泌腺瘤1型（MEN1）肿瘤抑制基因的种系突变会导致MEN1，这是一种罕见的家族性肿瘤综合征，与甲状旁腺增生、腺瘤及甲状旁腺功能亢进（HP）相关。在此，我们研究了MEN1基因在散发性和家族性孤立性HP中的作用。通过逆转录聚合酶链反应单链构象多态性筛查，在31例散发性原发性HP患者的腺瘤中有6例（19.3%）检测到MEN1编码序列的体细胞（而非种系）突变，但在16例因慢性肾衰竭所致继发性HP患者中未检测到。通过微卫星分析检测到，腺瘤中MEN1突变伴有11号染色体长臂13区MEN1位点杂合性缺失（LOH）。在HP腺瘤中未检测到MEN1基因5'区域（包含假定的MEN1启动子）内的DNA序列差异。有无MEN1突变的HP患者临床特征并无差异。分别在9.6%的原发性HP患者和25%的继发性HP患者中鉴定出杂合性MEN1基因多态性。在一个患有家族性孤立性HP的大家族中，MEN1种系突变249del4及LOH与HP表型及非内分泌恶性肿瘤易感性相关。我们认为，MEN1野生型基因表达的双等位基因体细胞缺失参与了散发性原发性HP腺瘤中一个临床上尚未明确的亚组的发病机制。MEN1基因分型可能有助于进一步明确家族性甲状旁腺功能亢进 - MEN1疾病复合体，但在散发性原发性HP中似乎并非必需。
