Mutch M G, Dilley W G, Sanjurjo F, DeBenedetti M K, Doherty G M, Wells S A, Goodfellow P J, Lairmore T C
Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Hum Mutat. 1999;13(3):175-85. doi: 10.1002/(SICI)1098-1004(1999)13:3<175::AID-HUMU1>3.0.CO;2-R.
Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests.
1型多发性内分泌腺瘤病（MEN 1）是一种家族性癌症综合征，其特征为甲状旁腺增生、垂体腺瘤以及胰腺和十二指肠的神经内分泌肿瘤。1997年，MEN1肿瘤抑制基因被确定，据报道，众多种系突变分布于整个基因。我们运用单链构象变异（SSCV）分析，在确诊为MEN 1的33个家族成员中寻找种系突变。SSCV分析揭示了25种构象变异，代表预计会导致正常Menin功能丧失的种系突变。确定了20种不同的疾病相关突变：5种导致潜在的异常RNA剪接，2种错义突变，7种无义突变，以及6种移码突变。通过RT-PCR和直接序列分析，对5种剪接突变中的2种鉴定并确认了异常剪接产物。所确定的20种（80%）突变中有16种此前未曾报道。在8个具有与MEN 1一致的体征和症状的家族中未发现突变。SSCV分析在76%（33个中的25个）被调查家族中发现了突变，从而表明SSCV分析是一种可靠的突变检测策略。本研究中确定的突变有五分之一涉及内含子序列，因此突出了在MEN1基因种系突变搜索中纳入内含子序列的重要性。在将基因研究转化为高效临床诊断测试时，对新的MEN 1家族进行特征分析时研究整个基因的必要性带来了挑战。
