Peutz-Jeghers综合征的STK11基因突变研究

发布时间：2018-06-12 14:17

本文选题：黑斑息肉综合征 + STK11基因　；参考：《川北医学院》2015年硕士论文

【摘要】：研究背景:黑斑息肉综合征,即PJ综合征(波伊茨-耶格综合征,Peutz-Jeghers syndrome,PJS,OMIM 175200),是一种临床上少见的常染色体显性遗传性疾病。临床主要表现为皮肤粘膜色素沉着性黑斑及胃肠道息肉,又被称为口周色素沉着(肠)息肉综合征(perioral pigmentationintestinal polyposis syndrome)。胃肠道息肉以错构瘤或腺瘤为主要病理类型,息肉可能会引起贫血、腹痛、肠梗阻、肠套叠等并发症,同时伴有高风险的胃肠或胃肠以外的恶性肿瘤。目前已确定STK11基因为PJ综合征的致病基因,该基因定位于19号染色体短臂13.3区域,编码丝氨酸/苏氨酸蛋白激酶(serine/threonine kinase LKB1/STK11),其作用是对细胞增殖、极性、功能和能量代谢等方面进行调控。STK11基因作为一种抑癌基因普遍存在于多种类型的恶性肿瘤之中。目前STK11基因新的突变在不断地被报道,不但丰富了STK11基因的突变谱,也为基因型和表型的相关性研究奠定了良好的理论基础。本研究收集中国四川省汉族人PJ综合征的3个家系和2个散发病例的临床资料,并对患者及其表型正常家庭成员采用DNA直接测序法进行STK11基因的突变检测。目的:分析中国四川省汉族人黑斑息肉综合征3个家系和2个散发病例的临床特点,检测STK11基因,发现新的致病突变。方法:收集3个PJS家系和2个散发病例详细的临床资料,采集PJS患者及其家庭成员的外周血标本,提取外周血细胞中的DNA,对STK11基因的全部外显子编码区及侧翼序列采用聚合酶链反应法(PCR)进行扩增,并通过对PCR产物使用DNA直接测序法进行序列分析,寻找新的致病突变。结果:在PJS家系中发现了2个新的杂合错义突变。家系1患者的STK11基因7号外显子发现c.908TG(p.Ile303Ser)错义突变。家系2患者的STK11基因9号外显子发现c.1251GT(p.Ala417Ser)错义突变。检测2个家系其他表型正常的家庭成员及100例无亲缘关系的正常个体,没有发现相应位点的突变。家系1和家系3患者的STK11基因7号内含子均发现1个杂合c.920+7GC多态位点(SNP)。散发病例没有发现STK11基因的突变。结论:研究结果显示家系1和家系2患者发病及出现恶变可能为STK11基因的c.908TG(p.Ile303Ser)和c.1251GT(p.Ala417Ser)2个错义突变所致。该研究发现了2个新的错义突变,丰富了STK11基因突变数据库的突变谱,为家系1和家系3患者的后代开展遗传咨询、基因诊断及产前诊断奠定了坚实的基础。
[Abstract]:Background: PJ syndrome, Peutz-Jeghers syndrome, PJSOMIM 175200, is a rare autosomal dominant hereditary disease. The clinical manifestations are pigmented melanoma and gastrointestinal polyp, also known as perioral pigmentationintestinal polyposis syndrome. The main pathological types of gastrointestinal polyps are hamartoma or adenoma. Polyps may cause anemia, abdominal pain, intestinal obstruction, intussusception and other complications, accompanied by high-risk gastrointestinal or non-gastrointestinal malignancies. The STK11 gene, which is located in the short arm 13.3 region of chromosome 19, encodes serine / threonine protein kinase serine / threonine kinase LKB1 / STK11, which is responsible for cell proliferation and polarity. As a tumor suppressor gene, STK11 gene is widely used in many types of malignant tumors. At present, new mutations of STK11 gene have been reported, which not only enrich the mutation profile of STK11 gene, but also lay a good theoretical foundation for the study of genotype and phenotypic correlation. In this study, the clinical data of 3 families and 2 sporadic cases of PJ syndrome in Han nationality of Sichuan Province, China were collected, and the mutation of STK11 gene was detected by DNA direct sequencing in patients and their normal phenotypic family members. Objective: to analyze the clinical characteristics of 3 families and 2 sporadic cases of black spot polyposis syndrome in Han nationality of Sichuan province of China, and to detect STK11 gene and find a new pathogenic mutation. Methods: the clinical data of 3 PJS families and 2 sporadic cases were collected. The peripheral blood samples of PJS patients and their family members were collected. DNA was extracted from peripheral blood cells and all exon coding regions and flanking sequences of STK11 gene were amplified by polymerase chain reaction (PCR). Results: two new heterozygous missense mutations were found in PJS pedigree. The missense mutation of exon 7 of STK11 gene was found in pedigree 1 patients. A missense mutation of exon 9 of STK11 gene was found in pedigree 2 patients. Two families with normal phenotypes and 100 unrelated normal individuals were detected and no mutation at the corresponding loci was found. A heterozygous c.9207GC polymorphism locus SNPN was found in intron 7 of STK11 gene in both pedigree 1 and pedigree 3. No mutation in STK 11 gene was found in sporadic cases. Conclusion: the results showed that the incidence and malignant change of family 1 and 2 patients were probably caused by two missense mutations of STK11 gene, c.908TGG, Ile303Serand c.1251GTp.Ala417Ser. This study found two new missense mutations, enriched the mutation spectrum of STK11 gene mutation database, and laid a solid foundation for genetic counseling, gene diagnosis and prenatal diagnosis for the offspring of family 1 and family 3 patients.
【学位授予单位】：川北医学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R596

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