Peutz-Jeghers综合征患者STK11及FHIT基因突变情况分析

发布时间：2018-05-20 01:40

本文选题：STK11基因 + FHIT基因　；参考：《河北北方学院》2015年硕士论文

【摘要】：Peutz-Jeghers综合征(Peutz-Jeghers syndrome,PJS),又名黑斑息肉病,是一种临床特征以胃肠道多发息肉及皮肤口腔黏膜黑褐色沉着斑为主的常染色体显性遗传病,约50%的PJS患者有家族史,发病率约1/200 000,具有较高的肿瘤易感性。分子遗传学研究表明,19号常染色体短臂即19p13.3区域的STK11基因(丝/苏氨酸蛋白激酶基因)是绝大多数PJS患者的主要致病基因,伴随基因的纯和或杂合缺失、框移突变或无义突变等,导致STK11基因功能的缺失。然而仍存在部分患者未检测到STK11基因突变位点,表明PJS患者可能存在STK11其他突变位点或存在除STK11外其他发病基因。研究曾表明位于3号染色体上的脆性组氨酸三联体(fragile histidine triad,FHIT)基因与PJS发病可能具有相关性,但局限于研究的样本量较小,尚需对大量的家系进行研究证实。且由于目前对FHIT基因在PJS患者突变情况的研究较少,所以FHIT是否是PJS的致病基因及其与其他突变基因间是否有关联,是否还存在其他致病基因等,尚需更深入的研究加以认证,进一步完善PJS的致病基因谱。以上也进一步说明PJS患者可能存在除STK11基因以外的其他基因突变。随着基因检测技术的不断提高,PJS的基因突变率和类型也会不断增多,对此病基因突变的深入研究,可进一步填补尚不完善的PJS患者基因突变谱。我们利用DNA直接测序技术对36例确诊的PJS患者及其直系亲属进行STK11及FHIT基因外显子区序列测定,将测序结果与基因库中正常STK11及FHIT基因序列比对,捕获新发突变位点,分析STK11及FHIT基因突变与PJS发病之间的关系及具有家族史患者和散发患者基因突变率的差异。对36例PJS患者行基因检测后发现22例患者存在STK11基因编码区的突变,其中7例突变类型被SNP基因库收录,被认为是基因的多态位点,余15例致病突变位点中除3例患者携带同一致病位点突变,及1例错义突变类型被研究者报道外,余11例突变未见文章报道,且未被SNP数据库收录,考虑为STK11新发致病基因位点。以上患者相关直系亲属未检测到此基因突变。STK11基因编码区突变阴性患者共14例。家族史组STK11基因突变率33.3%(6/18)与散发组STK11基因突变率50.0%(9/18)相比差异无统计学意义(P=0.50,P0.05);截短突变在具有家族史患者中的突变率27.8%(5/18)与其在散发患者间的突变率27.8%(5/18)相比差异无统计学意义(P=1.00,P0.05)。家族史与散发患者在黑斑首次出现的年龄及首次因肠梗阻或套叠行开腹手术治疗的时间之间相比差异无统计学意义(P=0.748/0.458,P0.05)。发生截短突变者因肠梗阻或套叠行外科手术的次数比错义突变者及非突变者多(P=0.033/0.038,P0.05),后两者间平均行外科手术的次数间相比差异无统计学意义(P=0.638,P0.05)。截短突变患者中一例伴有腺瘤性息肉变。通过对36例患者行FHIT基因外显子测序后,1例患者检测到FHIT基因外显子10(非编码区)杂合性基因突变位点,此突变类型未见相关报道,且不伴随STK11基因突变,可能通过对编码区的调控,改变蛋白功能或表达量等作用参与疾病的发生,结论尚需深入研究证实。其直系亲属未见此突变类型。10例患者发生FHIT基因编码区纯和或杂合基因多态位点(已报道)。STK11基因突变检测阳性患者同时不存在FHIT基因突变位点。研究结果进一步表明STK11基因突变是PJS(无论有家族史或散发患者)发病的主要致病基因,新发现的STK11截短突变或错义突变可能是PJS患者发病的遗传基础,完善了致病基因突变谱。FHIT基因突变可能参与PJS疾病的发生。发生STK11基因截短突变者比其他突变类型患者平均行外科手术的次数明显增多,这类患者还应尽早行胃镜、结肠镜、胶囊内镜或小肠镜等检查,了解息肉生长情况,尽量避免开腹手术的发生,以提高患者生活质量。也为下一步更深入研究STK11基因截短突变与PJ息肉(PJP)生长间的关系及与息肉癌变有无相关性奠定了基础。
[Abstract]:Peutz-Jeghers syndrome (Peutz-Jeghers syndrome, PJS), also known as black spotted polyposis, is an autosomal dominant hereditary disease characterized by multiple polyps in the gastrointestinal tract and dark brown spots in the oral mucosa of the skin. About 50% of PJS patients have a family history of about 1/ 200000 and have a higher susceptibility to cancer. Molecular genetics studies It is indicated that the STK11 gene (silk / threonine protein kinase gene) of the 19 autosomal short arm, the 19p13.3 region, is the main pathogenic gene in most of the PJS patients, with the deletion of the pure and heterozygous or heterozygous genes, the frame shift or the nonsense mutation, which leads to the deletion of the function of the STK11 gene. However, there are still some patients who have not detected the STK11 gene mutation position. Points, indicating that PJS patients may have other STK11 mutation sites or other genes except STK11. Studies have suggested that the fragile histidine three (FHIT) gene on chromosome 3 (fragile histidine triad, FHIT) may be associated with the pathogenesis of PJS, but it is limited to a small sample size and needs to be studied for a large number of families. It is confirmed that the mutation of the FHIT gene in PJS patients is less, so whether FHIT is the pathogenetic gene of PJS and whether it is associated with other mutant genes and whether there are other pathogenic genes still need more in-depth study to verify the pathogenic gene spectrum of the good PJS, and further explain the PJS. The patient may have other gene mutations other than the STK11 gene. With the continuous improvement of gene detection technology, the gene mutation rate and type of PJS are also increasing. The deep study of this gene mutation can further fill the mutation spectrum of the imperfect PJS patients. We use DNA direct sequencing technology for 36 cases of PJS confirmed. The STK11 and FHIT exons of the patients and their immediate family were sequenced. The sequencing results were compared with the normal STK11 and FHIT gene sequences in the gene bank to capture the new mutation sites. The relationship between the STK11 and FHIT gene mutations and the incidence of PJS and the difference of gene mutation rates with family history and sporadic patients were analyzed. 36 cases of PJS were found. After gene detection, 22 patients were found to have a mutation in the STK11 gene coding region. 7 of the mutations were included in the SNP gene pool, which were considered to be the polymorphic loci of the gene. In the remaining 15 cases, 3 patients carried the same unanimous site mutation, and 1 cases of missense mutation were reported by the researchers, and the remaining 11 cases had no mutation. In the chapter, it was not included in the SNP database and was considered as a new pathogenetic locus of STK11. The related direct relatives of the patients were not detected in 14 cases of mutation negative patients with.STK11 gene mutation. The mutation rate of STK11 gene in family history group (6/18) was not statistically significant compared with the mutation rate of STK11 based mutation rate 50% (9/18) in the sporadic group (9/18). P=0.50, P0.05); the mutation rate of the truncated mutation in the family history 27.8% (5/18) was not statistically significant compared to the mutation rate of 27.8% (5/18) among the sporadic patients (P=1.00, P0.05). The family history and sporadic patients were compared with the first age of the black spot and the difference between the first time of the intestinal obstruction or the time of the operation of the overlay operation. There was no statistical significance (P=0.748/0.458, P0.05). The number of truncated mutants caused by intestinal obstruction or overlapping surgery was more than that of missense mutants and non mutants (P=0.033/0.038, P0.05), and there was no statistically significant difference between the average number of surgical operations in the latter two (P=0.638, P0.05). One of the patients with truncated mutations was accompanied by adenoma. After FHIT gene exon sequencing in 36 patients, 1 patients detected heterozygous gene mutation loci of exon 10 (non coding region) of FHIT gene, which had not been reported, and did not accompany STK11 gene mutation. It may be involved in the disease by regulating the coding region, changing the function of protein or expression of protein. It is still necessary for further study to confirm that the direct relatives have not seen this mutation type.10 patients with the FHIT gene coding region and the polymorphic loci of the heterozygous gene (reported) that the.STK11 gene mutation test positive patients do not have the FHIT mutation site at the same time. The results show that the mutation of the STK11 gene is PJS (no matter family history). The main pathogenic gene of the disease, the newly discovered STK11 truncation or missense mutation may be the genetic basis of the PJS patients, and the mutation spectrum.FHIT mutation may be involved in the occurrence of PJS disease. The number of STK11 gene truncated mutations is more than the average number of surgery in other patients with other mutations. In addition, these patients should also perform early gastroscopy, colonoscopy, capsule endoscopy, or small enteroscopy, to understand the growth of polyps, to avoid open surgery, to improve the quality of life of the patients, and to further study the relationship between the STK11 gene truncation and the growth of PJ polyps (PJP) and whether there is a correlation with the cancer of polyps. Set the foundation.
【学位授予单位】：河北北方学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R596.1

【参考文献】