本文選題：馬凡綜合征　切入點(diǎn)：FBN基因　出處：《中國(guó)病理生理雜志》2016年03期 　論文類型：期刊論文

【摘要】：目的:本研究對(duì)2個(gè)不同馬凡綜合征(Marfan syndrome)的小家系進(jìn)行致病基因FBN1的編碼區(qū)和剪切位點(diǎn)突變檢測(cè),以尋找致病的突變,并初步探索馬凡綜合征基因型-表型的關(guān)聯(lián)。方法:通過(guò)臨床檢查、實(shí)驗(yàn)室檢查及心臟超聲檢查確診2個(gè)無(wú)血緣關(guān)系的家庭中原疑似為馬凡綜合征的3例患者。運(yùn)用新一代測(cè)序?qū)蚁?的疑似患者行FBN1基因的全外顯子組測(cè)序,并對(duì)檢出的致病性遺傳變異進(jìn)行Sanger驗(yàn)證及在所有家系成員中驗(yàn)證;對(duì)于家系2的存活成員,本研究直接進(jìn)行PCR擴(kuò)增FBN1基因的所有編碼區(qū)及剪切位點(diǎn),對(duì)產(chǎn)物進(jìn)行直接Sanger測(cè)序。另外在50個(gè)正常對(duì)照中對(duì)新發(fā)現(xiàn)的突變位點(diǎn)進(jìn)行基于PCR產(chǎn)物的測(cè)序分析,以排除多態(tài)性;并對(duì)實(shí)驗(yàn)結(jié)果行生物信息學(xué)分析。結(jié)果:所有存活的疑似患者均確診為馬凡綜合征。在家系1中,我們檢測(cè)到了一個(gè)FBN1基因數(shù)據(jù)庫(kù)中尚未報(bào)道的新突變c.4685GA(p.Cys1562Tyr),并且患者父母和同胞姐姐均未檢測(cè)到此變異,故此突變?yōu)橐粋�(gè)新生突變。該錯(cuò)義突變使第1 562位上極性中性的含硫的半胱氨酸被極性中性的含羥苯基的酪氨酸所替代,影響了fibrillin-1蛋白一個(gè)TGF-β結(jié)合結(jié)構(gòu)域,導(dǎo)致蛋白質(zhì)的二級(jí)結(jié)構(gòu)發(fā)生改變。家系2含父母及一對(duì)同卵雙胎患者,其中一患者已去世。我們?cè)诖婊罨颊邫z測(cè)到1個(gè)FBN1基因的已報(bào)道致病突變c.3706TC(p.Cys1236Arg),該突變?cè)诨颊吒改钢胁淮嬖?故也為新生突變。結(jié)論:本文報(bào)道了一例FBN1基因的新突變及另一例由FBN1基因已知突變引起的馬凡綜合征,二者皆為新生突變,并在家系中進(jìn)行了基因型-表型的比較,表明家系1的新突變可能與經(jīng)典馬凡綜合征的表型相關(guān),而家系2的已知突變確和新生兒重癥馬凡綜合征表型相關(guān)。
[Abstract]:Objective: to detect the coding region and shear site mutation of the FBN1 gene in two different Marfan syndrome lines, in order to search for the pathogenic mutation. And to explore the relationship between genotype and phenotype of Marfan syndrome. Laboratory examination and echocardiography confirmed 3 cases of suspected Marfan syndrome in 2 unrelated families. The whole exon group of FBN1 gene was sequenced by a new generation of sequencing. The pathogenicity genetic variation was verified by Sanger and among all the family members. For the surviving members of family 2, all coding regions and splicing sites of FBN1 gene were directly amplified by PCR. In addition, the new mutation sites were sequenced based on PCR products in 50 normal controls to exclude polymorphism. Bioinformatics analysis was performed on the results of the experiment. Results: all the suspected survivors were diagnosed with Marfan syndrome. We detected a new mutation, c.4685GAp.Cys1562TyrN, which has not been reported in a FBN1 gene database, and neither the patient's parents nor sibling sisters have detected this mutation. The missense mutation resulted in the substitution of the polar neutral cysteine containing sulfur with the polar neutral tyrosine containing hydroxyphenyl, which affected a TGF- 尾 binding domain of the fibrillin-1 protein. Family 2 contains parents and a pair of identical twins, one of whom is dead. We detected a reported FBN1 gene mutation in surviving patients, c. 3706 TCU p.Cys1236 Arg.com, which is not present in patients' parents. Conclusion: a new mutation of FBN1 gene and another case of Marfan syndrome caused by known mutation of FBN1 gene are reported. It was suggested that the new mutation of family 1 might be related to the phenotype of classical Marfan syndrome, while the known mutation of family 2 was related to the phenotype of neonatal severe Marfan syndrome.
【作者單位】： 中山大學(xué)中山醫(yī)學(xué)院醫(yī)學(xué)遺傳學(xué)教研室;中山大學(xué)疾病基因組研究所;廣州市婦女兒童醫(yī)療中心 心臟中心;廣州市公安局白云區(qū)分局刑警大隊(duì)技術(shù)中隊(duì);廣州市公安局黃埔區(qū)分局;中山大學(xué)新華學(xué)院;華大基因;
【基金】：國(guó)家自然科學(xué)基金資助項(xiàng)目(No.31471193)
【分類號(hào)】：R725.9
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本文編號(hào)：1614070