發(fā)布時間：2018-05-20 01:40

  本文選題：STK11基因 + FHIT基因��； 參考：《河北北方學院》2015年碩士論文

【摘要】：Peutz-Jeghers綜合征(Peutz-Jeghers syndrome,PJS),又名黑斑息肉病,是一種臨床特征以胃腸道多發(fā)息肉及皮膚口腔黏膜黑褐色沉著斑為主的常染色體顯性遺傳病,約50%的PJS患者有家族史,發(fā)病率約1/200 000,具有較高的腫瘤易感性。分子遺傳學研究表明,19號常染色體短臂即19p13.3區(qū)域的STK11基因(絲/蘇氨酸蛋白激酶基因)是絕大多數(shù)PJS患者的主要致病基因,伴隨基因的純和或雜合缺失、框移突變或無義突變等,導致STK11基因功能的缺失。然而仍存在部分患者未檢測到STK11基因突變位點,表明PJS患者可能存在STK11其他突變位點或存在除STK11外其他發(fā)病基因。研究曾表明位于3號染色體上的脆性組氨酸三聯(lián)體(fragile histidine triad,FHIT)基因與PJS發(fā)病可能具有相關性,但局限于研究的樣本量較小,尚需對大量的家系進行研究證實。且由于目前對FHIT基因在PJS患者突變情況的研究較少,所以FHIT是否是PJS的致病基因及其與其他突變基因間是否有關聯(lián),是否還存在其他致病基因等,尚需更深入的研究加以認證,進一步完善PJS的致病基因譜。以上也進一步說明PJS患者可能存在除STK11基因以外的其他基因突變。隨著基因檢測技術的不斷提高,PJS的基因突變率和類型也會不斷增多,對此病基因突變的深入研究,可進一步填補尚不完善的PJS患者基因突變譜。我們利用DNA直接測序技術對36例確診的PJS患者及其直系親屬進行STK11及FHIT基因外顯子區(qū)序列測定,將測序結果與基因庫中正常STK11及FHIT基因序列比對,捕獲新發(fā)突變位點,分析STK11及FHIT基因突變與PJS發(fā)病之間的關系及具有家族史患者和散發(fā)患者基因突變率的差異。對36例PJS患者行基因檢測后發(fā)現(xiàn)22例患者存在STK11基因編碼區(qū)的突變,其中7例突變類型被SNP基因庫收錄,被認為是基因的多態(tài)位點,余15例致病突變位點中除3例患者攜帶同一致病位點突變,及1例錯義突變類型被研究者報道外,余11例突變未見文章報道,且未被SNP數(shù)據庫收錄,考慮為STK11新發(fā)致病基因位點。以上患者相關直系親屬未檢測到此基因突變。STK11基因編碼區(qū)突變陰性患者共14例。家族史組STK11基因突變率33.3%(6/18)與散發(fā)組STK11基因突變率50.0%(9/18)相比差異無統(tǒng)計學意義(P=0.50,P0.05);截短突變在具有家族史患者中的突變率27.8%(5/18)與其在散發(fā)患者間的突變率27.8%(5/18)相比差異無統(tǒng)計學意義(P=1.00,P0.05)。家族史與散發(fā)患者在黑斑首次出現(xiàn)的年齡及首次因腸梗阻或套疊行開腹手術治療的時間之間相比差異無統(tǒng)計學意義(P=0.748/0.458,P0.05)。發(fā)生截短突變者因腸梗阻或套疊行外科手術的次數(shù)比錯義突變者及非突變者多(P=0.033/0.038,P0.05),后兩者間平均行外科手術的次數(shù)間相比差異無統(tǒng)計學意義(P=0.638,P0.05)。截短突變患者中一例伴有腺瘤性息肉變。通過對36例患者行FHIT基因外顯子測序后,1例患者檢測到FHIT基因外顯子10(非編碼區(qū))雜合性基因突變位點,此突變類型未見相關報道,且不伴隨STK11基因突變,可能通過對編碼區(qū)的調控,改變蛋白功能或表達量等作用參與疾病的發(fā)生,結論尚需深入研究證實。其直系親屬未見此突變類型。10例患者發(fā)生FHIT基因編碼區(qū)純和或雜合基因多態(tài)位點(已報道)。STK11基因突變檢測陽性患者同時不存在FHIT基因突變位點。研究結果進一步表明STK11基因突變是PJS(無論有家族史或散發(fā)患者)發(fā)病的主要致病基因,新發(fā)現(xiàn)的STK11截短突變或錯義突變可能是PJS患者發(fā)病的遺傳基礎,完善了致病基因突變譜。FHIT基因突變可能參與PJS疾病的發(fā)生。發(fā)生STK11基因截短突變者比其他突變類型患者平均行外科手術的次數(shù)明顯增多,這類患者還應盡早行胃鏡、結腸鏡、膠囊內鏡或小腸鏡等檢查,了解息肉生長情況,盡量避免開腹手術的發(fā)生,以提高患者生活質量。也為下一步更深入研究STK11基因截短突變與PJ息肉(PJP)生長間的關系及與息肉癌變有無相關性奠定了基礎。
[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.
【學位授予單位】：河北北方學院
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R596.1

【參考文獻】

相關期刊論文 前1條

1 顧國利;魏學明;徐麗梅;王石林;;Peutz-Jeghers綜合征預防性治療的研究[J];胃腸病學和肝病學雜志;2012年04期

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本文編號：1912638