本文選題：先天性甲狀腺功能減低癥　切入點(diǎn)：甲狀腺球蛋白基因　出處：《西北大學(xué)》2017年碩士論文

【摘要】：先天性甲狀腺功能減低癥(Congenital hypothyroidism,CH)是一種常見的嬰幼兒內(nèi)分泌疾病,可能導(dǎo)致兒童生長緩慢及智力發(fā)育遲緩。以前的研究發(fā)現(xiàn)許多與甲狀腺素合成相關(guān)的基因的突變與CH的發(fā)生相關(guān)。甲狀腺球蛋白基因(TG)是甲狀腺激素合成的基質(zhì),在前人研究中TG突變使得甲狀腺素合成和分泌過程受到影響,是導(dǎo)致CH的重要原因之一。本研究以來自西安地區(qū)的130例CH患者為和100例健康個(gè)體為研究對象,采用高通量測序的方法對CH患者的TG基因的外顯子進(jìn)行檢測。篩查突變位點(diǎn),研究西北地區(qū)人群TG的突變譜,分析TG基因突變在CH發(fā)病過程中的分子機(jī)制。在130例CH患者中,共發(fā)現(xiàn)24個(gè)可能導(dǎo)致CH發(fā)病的TG突變,4為個(gè)無義突變,3個(gè)為剪接突變和17個(gè)為錯(cuò)義突變。新發(fā)現(xiàn)的突變有8個(gè),包括c.4641_4641delG,c.2060_2060delG,c.2864_2864delA,c.6840_6843delTTGT,c.3139+2TC,c.3634-ldelG,c.1514GA,c.7182CG,它們在健康對照組中的頻率均小于1%。計(jì)算生物學(xué)預(yù)測結(jié)果表明12種突變?yōu)橛泻ν蛔?12種為良性突變。將人的與牛,豬,猩猩,小鼠和大鼠的TG蛋白進(jìn)行同源性比較,發(fā)現(xiàn)突變p.Arg1202Cys,p.Pro2236Leu,p.Ile2394Met,p.Arg2585Trp 處于 TG 的保守區(qū)。而 2236,2394,2585位氨基酸處于TG蛋白的功能域中。利用蛋白質(zhì)同源建模,對其三維結(jié)構(gòu)的分析發(fā)現(xiàn),c.6707CT(p.Pro2236Leu)和 c.7753CT(p.Arg2585Trp)突變均會(huì)導(dǎo)致蛋白結(jié)構(gòu)的改變。最后根據(jù)ACMG對序列變異致病性的指導(dǎo)原則和標(biāo)準(zhǔn),結(jié)合已有的證據(jù),對24種突變做了致病等級劃分。結(jié)果發(fā)現(xiàn),其中7個(gè)突變?yōu)榭芍虏〉耐蛔?4種為無義突變,3種為剪接突變。7個(gè)意義未明的突變的錯(cuò)義突變,而其他10種錯(cuò)義突變則為良性或可能良性的突變。通過本研究的結(jié)果可以看出,在中國西北地區(qū)CH患者中,TG基因的突變頻率為23%,其中雜合突變86.7%,復(fù)合雜合突變13.3%。兩個(gè)復(fù)合雜合突變除c.7182CG/c.3035CT和c.2560CT/c.1919AG外均為重度CH患者且伴有甲狀腺腫,說明TG突變可能是導(dǎo)致這兩個(gè)患者CH發(fā)生的原因。但部分未攜帶有TG突變的患者也表現(xiàn)為重度CH,因而,可能存在其他的CH相關(guān)的基因突變,需要進(jìn)一步探索。總之,本研究利用高通量測序的方法研究了西北地區(qū)CH患者的TG基因的突變,擴(kuò)大了TG基因的突變譜,同時(shí),初步確立了部分TG突變與臨床表型的關(guān)系,對進(jìn)一步研究CH的致病機(jī)制有重要的價(jià)值。
[Abstract]:Congenital hypothyroidism is a common endocrine disease in infants. Previous studies have found that mutations in many genes associated with thyroxine synthesis are associated with the development of Ch. Thyroglobulin gene (TGG) is the matrix for thyroid hormone synthesis. In previous studies, TG mutation affected the synthesis and secretion of thyroxine, which was one of the important causes of Ch. 130 Ch patients from Xi'an and 100 healthy individuals were studied in this study. The exon of TG gene in Ch patients was detected by high-throughput sequencing. The mutation sites of TG gene were screened, and the molecular mechanism of TG gene mutation in Ch was analyzed in 130 patients with Ch by studying the mutation spectrum of TG in Northwest China population, and analyzing the molecular mechanism of TG gene mutation in the pathogenesis of Ch. A total of 24 TG mutations, including 3 splicing mutations and 17 missense mutations, were found to cause Ch. Including c.4641delGng c.2060delGngc28642864delAn c.684040C 6843delTTGTnc. 31392TCU c.3634-ldelGnc1514GAc.7182CG. the predicted results of computational biology indicate that 12 mutants are harmful mutations, 12 are benign mutations, and the TG proteins of human beings are compared with those of cattle, pigs, orangutans, orangutans and rats, and the results of the prediction of computational biology indicate that 12 of them are benign mutations, and the TG proteins of human beings are compared with those of cattle, pigs, orangutans, orangutans and rats. It was found that the mutant p.Arg1202Cysn p.Pro2236Leuanp.Ile2394Metp.Arg2585Trp was in the conserved region of TG, while the amino acid at 2236H2394C 2585 was located in the functional domain of TG protein. It was found that the mutation of C. 6707CTp.Pro2236Leu and c.7753CTU p.Arg2585Trp) would result in the change of protein structure. Finally, according to the guidelines and criteria of ACMG for the pathogenicity of sequence variation, combined with the existing evidence, The pathogenicity grades of 24 mutations were classified. The results showed that 7 mutations were pathogenicity, 4 were nonsense mutations, 3 were splicing mutations, and 7 were undefined missense mutations. The other 10 missense mutations are benign or possibly benign. The mutation frequency of triglyceride gene in Ch patients in Northwest China was 23. The heterozygosity mutation was 86. 7% and the complex heterozygosity mutation was 13. 3%. The two complex heterozygous mutations, except c.7182CG/c.3035CT and c.2560CT/c.1919AG, were both severe Ch patients and accompanied with goiter. This indicates that TG mutation may be the cause of Ch in these two patients. However, some patients without TG mutation also present severe CH.Therefore, there may be other CH-related gene mutations that need further exploration. In this study, high-throughput sequencing was used to study the mutation of TG gene in Ch patients in Northwest China, and to enlarge the mutation spectrum of TG gene. At the same time, the relationship between some TG mutations and clinical phenotypes was preliminarily established. It is of great value to further study the pathogenesis of Ch.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R725.8

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