一例肝豆?fàn)詈俗冃约彝サ腁TP7B基因突變研究
發(fā)布時間：2018-05-30 17:08
本文選題：肝豆?fàn)詈俗冃?/strong> + ATP7B基因��； 參考：《青島大學(xué)》2017年碩士論文
【摘要】：目的通過對一例肝豆?fàn)詈俗冃渭蚁档幕蚍治?驗證該病的遺傳方式。同時對近年來國內(nèi)所報道的肝豆?fàn)詈俗冃灾虏』虿±M行回顧性分析,研究其在基因型與表現(xiàn)型之間的關(guān)系。從而為該病在臨床中引起重視,減少誤診漏診率做出貢獻,為尋找肝豆?fàn)詈俗冃孕碌脑\療思路提供方向。方法首先通過人類基因組DNA提取,聚合酶鏈反應(yīng)(PCR)和DNA測序等分子生物學(xué)技術(shù)檢測ATP7B突變。在二代測序得出結(jié)果后,通過Sanger一代測序驗證前者結(jié)果的準(zhǔn)確性。對先證者及其父母進行生化、血常規(guī)等實驗室以及影像學(xué)檢查,比較ATP7B基因檢測結(jié)果及其性別,年齡,臨床類型,血清銅藍蛋白和尿銅的分析,分析其基因型和臨床表型。其次通過回顧性分析肝豆?fàn)詈俗冃曰颊?分析中國人ATP7B基因型的熱點突變以及高頻突變的分布規(guī)律;根據(jù)病人的臨床資料,如年齡、性別、發(fā)病類型以及患病的嚴(yán)重程度,分析該病基因型與表現(xiàn)型的關(guān)系,以期得到確定性結(jié)果。結(jié)果患兒母親ATP7B基因第8號外顯子發(fā)生了錯義突變(c.2333GT),突變類型為R778L;患兒父親ATP7B基因第11號外顯子發(fā)生了錯義突變(c.2621CT),突變類型為A874V。兩位突變基因攜帶者將致病基因遺傳給子代,致使先證者患病。一代測序結(jié)果得出相同的結(jié)果。實驗室檢查結(jié)果表明,先證者肝功能異常。通過對近5年的相關(guān)文獻進行回顧性分析,我們總共得到255例患者。發(fā)現(xiàn)中國人的突變熱點為R778L,突變率為38.04%。主要的突變類型為錯義突變,突變率為92.97%。不同基因型之間,表現(xiàn)型并無明顯差別。結(jié)論肝豆?fàn)詈俗冃曰颊呃^承了作為致病基因攜帶者的父母的隱性基因從而患病,即使突變基因基因型多種多樣,但其發(fā)病機制以及臨床表現(xiàn)并無明顯差別。先證者出現(xiàn)肝功能異常,可見該病首先累積肝臟。其父母的相關(guān)實驗室檢查較為正常,可見單純攜帶致病基因并不會對造成相關(guān)蛋白表達的異常。影像學(xué)檢查顯示先證者各臟器大小正常,可見如果能在發(fā)病早期做到及時的確診以及治療,會有效干預(yù)病程進展,且經(jīng)過后續(xù)治療預(yù)后效果非常好。在回顧的255例患者當(dāng)中,有251例檢測出基因突變,仍有4例未能檢測出突變,其原因可能是這4例患者的突變并非定位于外顯子上,可能存在于內(nèi)含子或外顯子與內(nèi)含子連接處。如果能夠獲得先證者完整家系的基因分析是最好不過,但在實際當(dāng)中要完成十分困難。因此對于先證者父母的同胞來說,他們也可能是致病基因的攜帶者。因此對于潛在的攜帶者,進行基因檢測就十分必要。特別是對于即將生育下一代的,檢查自己是否是致病基因的攜帶者,就更加重要。同時對于已經(jīng)生育患病兒童的父母,在生第二胎之前,對胎兒進行基因篩查,進行產(chǎn)前基因咨詢,是十分必要的。
[Abstract]:Objective to verify the genetic pattern of the disease by genetic analysis of a family with hepatolenticular deformities. The relationship between genotypes and phenotypes of hepatolenticular degeneration genes reported in recent years was analyzed retrospectively. Thus, it can make a contribution to the clinical attention, reduce the rate of misdiagnosis and miss diagnosis, and provide the direction for finding a new diagnosis and treatment of hepatolenticular degeneration. Methods Human genomic DNA was extracted, polymerase chain reaction (PCR) and DNA sequencing were used to detect ATP7B mutation. After the second generation sequencing, the accuracy of the former result was verified by Sanger generation sequencing. Biochemistry, blood routine examination and imaging examination were performed on the proband and their parents. The results of ATP7B gene analysis, sex, age, clinical type, serum ceruloplasmin and urine copper were compared, and their genotypes and clinical phenotypes were analyzed. Secondly, by retrospective analysis of patients with hepatolenticular degeneration, the hot spot mutation and high frequency mutation of ATP7B genotypes in Chinese were analyzed, according to the clinical data of the patients, such as age, sex, type of disease and severity of the disease. The relationship between genotypes and phenotypes of the disease was analyzed in order to obtain deterministic results. Results the missense mutation in exon 8 of ATP7B gene was found in the mother and the mutation type was R778L, and the missense mutation in exon 11 of the father ATP7B gene was identified as A874V. Two carriers of mutated genes passed on the disease-causing genes to their offspring, causing the proband to become ill. A generation of sequencing results yielded the same results. The results of laboratory examination showed that the liver function of the proband was abnormal. A total of 255 patients were obtained by retrospective analysis of the literature in the last 5 years. It was found that the hot spot of mutation in Chinese was R778L, and the mutation rate was 38.04L. The main mutation type was missense mutation, the mutation rate was 92.97%. There was no significant difference in phenotype between genotypes. Conclusion the patients with hepatolenticular degeneration inherited the recessive genes of their parents as carriers of pathogenic genes, and had no significant difference in their pathogenesis and clinical manifestations, even though the mutation genotypes were varied. The liver function is abnormal in the proband, and the liver accumulates first. The relative laboratory tests of their parents showed that simply carrying pathogenic genes did not cause abnormal expression of related proteins. Imaging examination showed that the size of the organs of the proband was normal. It can be seen that if we can make timely diagnosis and treatment in the early stage of the disease, we can effectively intervene the progression of the disease course, and the prognosis is very good after the follow-up treatment. Of the 255 patients reviewed, 251 detected mutations and 4 failed to detect mutations, possibly because the mutations were not located in the exon. It may exist at the junction of intron or exon with intron. Genetic analysis of the proband's complete family is best, but is difficult to complete in practice. Therefore, for the proband's parents, they may also be carriers of the pathogenic gene. Therefore, for potential carriers, genetic testing is very necessary. Especially for those about to bear the next generation, it is even more important to check if you are carrying the disease-causing genes. At the same time, it is necessary for parents who have already given birth to sick children to carry out genetic screening and prenatal genetic counseling before giving birth to the second child.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R742.4
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