Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders
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DOI：
10.1086/301953
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发表时间：
1998-08-01
影响因子：
9.8
通讯作者：
Calender, A
中科院分区：
文献类型：
--
作者：
Giraud, S;Zhang, CX;Calender, A
多发性内分泌肿瘤1型（MEN1）是常染色体显性综合征，易发生甲状旁腺、内分泌胰腺、垂体前叶、肾上腺和弥漫性神经内分泌组织的肿瘤。通过连锁分析和杂合性缺失，MEN1基因被分配到染色体11q13上，最近被定位克隆鉴定。在本研究中，通过对MEN1基因编码区和未翻译外显子1的异双工和序列分析，对84个MEN1或MEN1相关遗传性内分泌肿瘤家庭和/或分离患者进行MEN1种系突变筛查。在47/54 (87%)MEN1家族、9/11（82%）分离MEN1患者和6/19（31.5%）非典型MEN1相关遗传病例中发现了种系MEN1改变。我们在总共62个MEN1种系改变中鉴定了52个不同的突变。52个突变中有35个是移帧突变和无义突变，预计会编码截断的MEN1蛋白。我们在整个编码序列中发现了8个错义突变和5个帧内缺失。家族性MEN1中有6个突变不止一次。对具有相同突变的家庭进行单倍型分析表明，这些事件主要反映了独立的突变事件。在7/54 (13%)MEN1家族、2/11 (18%)MEN1分离病例、13/19 (68.5%)MEN1相关病例和1例家族性孤立性甲状旁腺功能亢进亲属中未发现MEN1种系突变。鉴定出220名基因携带者（167名受影响，53名未受影响）。未发现基因型与表型相关的证据。年龄相关的外显率在30岁时估计为95%。我们的研究结果增加了MEN1种系突变的多样性，并为MEN1和临床相关病例的遗传筛查提供了新的工具。
Multiple endocrine neoplasia type 1 (MEN1) is autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germline mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68.5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.