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多发性内分泌腺瘤病2A型家系临床特点分析及RET基因突变研究

The clinical features of multiple endocrine neoplasia type 2A (MEN2A) and ret proto-oncogene mutation study
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摘要 目的检测互不相关的3个多发性内分泌腺瘤病2A型(MEN2A)家系中RET原癌基因突变情况,以探寻其发病的分子机制,同时总结其临床特点。方法收集3个MEN2A家系,共有8例MEN2A患者,3个家系有28位同意进行基因检测,提取28位外周血基因组DNA,对RET原癌基因21个外显子进行聚合酶链反应(PCR),PCR产物进行直接测序,对发现新的突变点进一步进行克隆测序。结果家系1RET原癌基因存在外显子11的C634R突变,家系2为C634Y突变,家系3的4例MEN2A患者均存在D631密码子(GAC)的杂合缺失,碱基序列由TGC∧GACGAGCTG变为TGCGAGCTG,导致代表天冬氨酸的D631的缺失,即del D631。8例MEN2A患者中7例有MTC(87.5%),8例有PCC(100%),未发现有HPT的发生,其中6例(75%)患者是以PCC起病,而且PCC中7例(87.5%)为双侧。结论本研究结果提示中国大陆MEN2A家系存在C634Y突变,也有exon11的D631杂合缺失突变,其中RET基因第11号外显子的D631缺失突变(delD631)是首例报道。D631 del临床特点为发病年龄较迟,肾上腺嗜铬细胞瘤可先于甲状腺髓样癌的发生。 Objective To investigate the molecular pathogenesis of multiple endocrine neoplasia 2A (MEN2A) ,three unrelated families from China's Mainland were studied. Methods Three unrelated families,among of which 8 were clinically diagnosed MEN2A patients. There were 28 subjects in the three families consented to perform the gene scanning. Genomic DNA of the 28 subjects were extracted from peripheral leukocytes. The 21 exons of the RET proto-oncogene were amplified using polymerase chain reaction method, and the products were detected by direct sequencing. Further cloning and sequencing were performed for novel mutation. The mutated loci were also screened in the corresponding family members. All the identified mutations were compared with known RET proto-oncogene mutations in human gene mutation database in cardiff. Results In family 1, a C634R mutation at exon 11 of the RET proto-oncogene was detected,while C634Y at the same locus was found in family 2. A novel heterozygous mutation of 3-bp (GAC) deletion at coden 631 ( del D631 ) of exon 11 was identiffed in the 4 MEN2A patients of family 3, leading to a change of sequence from TGCGACGAGCTG to TGCGAGCTG, resulting in the deletion of an asparagine at the locus. Medullary thyroid carcinoma ( MTC ) was found in 7 (87. 5 % )patients, and pheochromocytoma was-found in all( 100% )of the 8 MEN2A patients. Hyperplasia or adenoma of the parathyroid gland was not found in any of these cases. Among them, pheochromocytoma was the initial demonstration of the syndrome in 6 patients (75 % ), and bilateral pheochromoeytomas were found in 7 of them ( 87. 5 % ). Conclusion The study indicated that there was C634Y mutation relating to MEN2A syndrome, as well as heterozygous deletion mutation at D631 of exon 11, the latter of which was the first report to our knowledge.
出处 《中国临床实用医学》 2008年第10期3-6,共4页 China Clinical Practical Medicine
基金 广东省自然科学基金资助(项目编号:4009414) 广东省科技计划项目基金资助(项目编号:2007B031504004)
关键词 多发性内分泌腺瘤2A型 RET原癌基因 缺失突变 Multiple endocrine neoplasia type 2A RET proto-oncogene Deletion mutation
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