本文選題：Perrault綜合征 + C10ORF2��； 參考：《山東大學(xué)》2016年博士論文

【摘要】：第一章線粒體相關(guān)基因C10ORF2在家族性原發(fā)性卵巢功能不全合并感音神經(jīng)性耳聾(Perrault綜合征)發(fā)病中的作用和機制研究第—節(jié)Perrault綜合征家系全外顯子組測序研究目的：原發(fā)性卵巢功能不全(POI)是一種高度異質(zhì)性、病因復(fù)雜的婦科內(nèi)分泌疾病,患者通常在40歲以前就出現(xiàn)閉經(jīng),發(fā)病率約為1%。該疾病的特點是原發(fā)性或繼發(fā)性閉經(jīng)并且伴隨不同程度的低雌激素癥狀。目前尚沒有可靠的早期診斷指標,也不能早期有效的預(yù)防該疾病的發(fā)生和進展,因而病因研究和早期識別高風(fēng)險人群是十分重要的。原發(fā)性卵巢功能不全主要分為綜合征型POI和非綜合征型POI兩種,并在兩種類型中分別篩選出了多個致病基因。其中已發(fā)現(xiàn)的綜合征型POI包括脆X綜合征、小瞼裂綜合征(BPES).半乳糖血癥、碳水化合物缺乏糖蛋白綜合征I型、Perrault綜合征(PS)等,通過全外顯子組測序發(fā)現(xiàn)Perrault綜合征患者的致病基因包括HARS2、LARS2、C10ORF2、CLPP等。Perrault綜合征患者在患有感音神經(jīng)性耳聾的同時,女性患者還伴有典型的原發(fā)性卵巢功能不全癥狀。我們對先證者及家系其他成員進行全外顯子組測序,以期發(fā)現(xiàn)新的POI致病基因。方法：對該Perrault綜合征中先證者、患病姐妹以及父母采用Agilent SureSelect Human All Exon.V5技術(shù)對全外顯子組進行測序,將檢出的全部單堿基改變、插入／缺失與公共數(shù)據(jù)庫比對排除已知多態(tài),之后檢出造成氨基酸改變的非同義突變,再根據(jù)孟德爾遺傳定律篩出候選位點。最后按照常染色體隱性遺傳的方式進行基因篩選,且在患者中篩選出共同的純合突變位點。結(jié)果：全外顯子組測序后發(fā)現(xiàn)了符合常染色體隱性遺傳的一個錯義突變位點,該突變位于C10ORF2基因的c.1388GA(p.R463Q)位點,屬于一個新發(fā)的錯義突變,該突變使該位置的氨基酸由精氨酸變?yōu)楣劝滨０�。患者為純合突�?并發(fā)生于編碼蛋白的解旋酶區(qū)域。C10ORF2基因的解旋酶作用對線粒體的復(fù)制至關(guān)重要,推測該突變導(dǎo)致的蛋白功能改變影響了細胞線粒體功能,從而導(dǎo)致了Perrault綜合征的發(fā)生。結(jié)論： 通過外顯子測序技術(shù)在C10ORF2基因的解旋區(qū)域內(nèi)發(fā)現(xiàn)了新發(fā)錯義突變位點,該基因突變的發(fā)現(xiàn)為從線粒體功能方面探索POI的機制研究提供了新的方向。第二節(jié)C10ORF2基因在原發(fā)性卵巢功能不全中的作用機制研究目的：在原發(fā)性卵巢功能不全伴隨感音神經(jīng)性耳聾患者(PS)家系中,我們通過全外顯子組測序發(fā)現(xiàn)了位于C10ORF2基因上的錯義突變位點c.1388GA(p.R463Q)。在既往研究中,發(fā)現(xiàn)位于同一位點的其他氨基酸改變導(dǎo)致患者嬰兒脊髓小腦發(fā)育不全的嚴重表現(xiàn)。C10ORF2基因編碼的DNA解旋酶參與了真核細胞內(nèi)線粒體復(fù)制過程,而線粒體作為顆粒細胞和卵母細胞內(nèi)含量豐富的細胞器,調(diào)節(jié)了顆粒細胞和卵母細胞的代謝、細胞周期和細胞信號轉(zhuǎn)導(dǎo)。但目前該基因功能與卵巢的關(guān)系尚無報道。本課題通過研究C10ORF2突變導(dǎo)致細胞線粒體功能發(fā)生的變化,探討(C10ORF2基因突變引發(fā)POI的致病機制。方法：通過收集Perrault綜合征患者家系外周血,提取先證者外周血液DNA,建立C100RF2基因c.1388GA(p.R463Q)位點突變的永生化淋巴細胞系,檢測患者外周血永生細胞內(nèi)線粒體ATP產(chǎn)生,線粒體拷貝數(shù)以及細胞內(nèi)ROS的生成等,研究C10ORF2基因突變導(dǎo)致的細胞線粒體功能變化。結(jié)果：通過提取患者外周血并構(gòu)建永生化淋巴細胞進行功能實驗,我們發(fā)現(xiàn)C10ORF2基因突變導(dǎo)致了細胞內(nèi)ATP產(chǎn)生減少,ROS水平升高,并發(fā)現(xiàn)C10ORF2基因突變的永生化淋巴細胞內(nèi)線粒體拷貝數(shù)也明顯低于正常人水平。這些實驗結(jié)果表明該基因突變嚴重影響了細胞內(nèi)線粒體的活力和氧化磷酸化水平,導(dǎo)致了線粒體功能障礙。結(jié)論：在C10ORF2基因中,c.1388GA(p.R463Q)位點突變嚴重影響了細胞的線粒體功能。如果該突變發(fā)生在卵巢內(nèi),將阻礙卵巢內(nèi)卵母細胞和顆粒細胞的正常能量代謝,使卵母細胞成熟障礙。如果線粒體功能嚴重缺陷,使細胞ATP生成減少及ROS累積增多,將導(dǎo)致卵母細胞無法代償而發(fā)生死亡。因此,C10ORF2基因突變導(dǎo)致的卵巢內(nèi)線粒體內(nèi)能量代謝障礙可能是導(dǎo)致POI的重要機制之一。第二章HELQ基因在原發(fā)性卵巢功能不全患者中的突變分析目的：原發(fā)性卵巢功能不全(POI)病因具有高度異質(zhì)性,多數(shù)患者病因尚不明確。我們發(fā)現(xiàn)POI和自然絕經(jīng)年齡以及早絕經(jīng)年齡具有共同的遺傳易感性,為POI的病因?qū)W研究提供了新的方向。有研究通過全基因組關(guān)聯(lián)分析發(fā)現(xiàn)了13個與絕經(jīng)年齡相關(guān)的位點,在隨后的生物信息學(xué)分析中發(fā)現(xiàn)8個候選基因與DNA損傷修復(fù)相關(guān),其中HELQ基因具有較高的POI風(fēng)險性,因此被列為POI的重要候選基因,它編碼了蛋白HEL308,是一個DNA依賴性的ATP酶及DNA解旋酶,并且與RAD51同源蛋白一起參與了DNA鏈間交聯(lián)反應(yīng)的修復(fù)。鏈間交聯(lián)反應(yīng)的修復(fù)需要細胞分裂間期S期檢查點和范可尼貧血途徑的共同協(xié)同作用來完成。Helq-/-基因敲除小鼠生育能力降低,且卵巢組織切片呈現(xiàn)明顯的萎縮現(xiàn)象。本研究旨在通過對漢族POI患者進行HELQ基因的外顯子測序,明確該基因在POI患者中的突變情況,為POI病因?qū)W研究及臨床遺傳咨詢與生育指導(dǎo)提供理論依據(jù)。方法：選取在2012至2014年就診于山東大學(xué)附屬生殖醫(yī)院的中國漢族POI患者192例,將其血液DNA提取后,進行HELQ基因全部外顯子及外顯子與內(nèi)含子鄰接部位測序。所測結(jié)果與數(shù)據(jù)庫中國漢族北方正常人群進行序列比對,用SPSS軟件將SNP位點的基因型和等位基因頻率進行統(tǒng)計分析。結(jié)果：在HELQ基因外顯子測序中發(fā)現(xiàn)6個單核苷酸多態(tài)位點,其中rs1494961, rs2047210兩個位點經(jīng)過統(tǒng)計分析后發(fā)現(xiàn),基因型和等位基因頻率與對照組相比沒有統(tǒng)計學(xué)差異,rs13141136,rs7665103,rs11099600,rs12645412與對照人群比較有統(tǒng)計學(xué)差異,但屬于同義改變。結(jié)論：首次在中國漢族原發(fā)性卵巢功能不全患者中篩查了HELQ基因的編碼序列,發(fā)現(xiàn)HELQ基因突變不是原發(fā)性卵巢功能不全的常見原因。第三章PRIM1基因在原發(fā)性卵巢功能不全患者中的突變分析及基因敲除小鼠研究第—節(jié)PRIM1基因在原發(fā)性卵巢功能不全患者中的突變分析目的：近年來越來越多的研究發(fā)現(xiàn)原發(fā)性卵巢功能不全和早絕經(jīng)之間具有共同的遺傳易感性,為探索POI的致病機制提供了一個新的方向。有研究通過全基因組關(guān)聯(lián)分析,發(fā)現(xiàn)了13個與絕經(jīng)年齡相關(guān)的位點,其中包括PRIM1基因。PRIM基因不僅與自然絕經(jīng)年齡密切相關(guān),并且后續(xù)在歐洲人群中的研究發(fā)現(xiàn)PRIM1基因的非同義多態(tài)性位點rs2277339與早絕經(jīng)和POI也有顯著相關(guān)性。PRIM1基因編碼的DNA引發(fā)酶主要參與DNA復(fù)制過程,在合成岡崎片段時通過促進合成RNA引物來完成DNA的合成。本研究旨在通過對192例中國漢族POI患者進行PRIM1編碼序列測定,從而確定該基因突變是否導(dǎo)致POI的發(fā)生。方法：選取2014年至2015年就診于山東大學(xué)附屬生殖醫(yī)院的192例POI病人為研究對象,應(yīng)用直接測序技術(shù)進行PRIM1基因編碼區(qū)域測序即基因突變篩查,所獲結(jié)果與Ensemble數(shù)據(jù)庫中正常中國北方人群作為對照組進行對比,用SPSS軟件將SNP位點的基因型和等位基因頻率進行統(tǒng)計分析。結(jié)果：在POI病人中篩查出3個已知SNP位點rs2277339,rs1131514和rs1026565,分別位于外顯子1,外顯子10和內(nèi)含子6中,它們的基因型和等位基因頻率在POI和對照組數(shù)據(jù)中相比沒有統(tǒng)計學(xué)差異。結(jié)論：PRIM1基因突變在中國漢族原發(fā)性卵巢功能不全患者中并不常見。雖然在歐洲人群中rs2277339位點與原發(fā)性卵巢功能不全相關(guān),但在中國漢族POI婦女中并無意義,可能由種族差異性或本研究的樣本量較少導(dǎo)致。PRIM1基因在POI發(fā)病中的作用尚需繼續(xù)深入研究。第二節(jié)Prim1基因敲除小鼠的生育力分析目的：在原發(fā)性卵巢功能不全的遺傳學(xué)研究中不僅需要基因組學(xué)的研究為尋找新的致病位點提供依據(jù),而探索POI致病機制過程中更需要動物體內(nèi)實驗的生物學(xué)支持。因此,在進行PRIM1基因篩查的同時,為了評估PRIMl基因在體內(nèi)的生理作用,我們構(gòu)建了Prim1基因敲除小鼠,研究該基因的缺失是否影響小鼠生長發(fā)育及生殖功能。方法：采用CRISPR/Cas9技術(shù),在該靶基因內(nèi)尋找Cas9切點,設(shè)計、構(gòu)建對應(yīng)的gRNA序列,測試其核酸內(nèi)切活性后,與Cas9-mRNA共同注射小鼠單細胞胚,繁育后取得F1代雜合子Prim1+/-小鼠。通過合籠后記錄生育子代數(shù),子代基因型比例,卵巢形態(tài),大小和卵巢內(nèi)各級卵泡數(shù)目等研究Prim1基因缺失對小鼠生殖系統(tǒng)的影響。結(jié)果：Prim1+/-小鼠合籠后沒有純合子Primr1-/-小鼠出生。在雜合子Prim1+/-小鼠研究中發(fā)現(xiàn),其子代數(shù)目、卵巢大小及卵巢內(nèi)各級卵母細胞數(shù)目等與野生型小鼠相比沒有明顯差異。結(jié)論:Prim1+/-小鼠與野生型小鼠比較沒有明顯生育力差異。沒有Prim1純合子子代出生,說明該基因的缺失可能嚴重影響了細胞的周期和DNA損傷修復(fù)過程而導(dǎo)致細胞凋亡的發(fā)生,使Prim1-/-小鼠胚胎死亡。在今后的研究中,可考慮構(gòu)建條件性Prim1基因敲除小鼠,從而研究該基因?qū)β殉补δ艿挠绊憽?br/>[Abstract]:Chapter 1 the role and mechanism of mitochondrial related gene C10ORF2 in the pathogenesis of familial primary ovarian dysfunction combined with sensorineural deafness (Perrault syndrome): the purpose of sequencing of the exon group of Perrault syndrome: primary ovarian dysfunction (POI) is a highly heterogeneous, complicated cause of the disease. Endocrine disorder, patients usually have amenorrhea before 40 years of age. The incidence of the disease is about 1%.. The disease is characterized by primary or secondary amenorrhea and with varying degrees of low estrogen symptoms. There is no reliable early diagnostic indicator and early and effective prevention of the occurrence and progress of the disease. It is very important to identify high risk people. Primary ovarian dysfunction is mainly divided into two types of syndrome type POI and non syndrome type POI, and multiple pathogenic genes are screened in two types. The found syndrome type POI includes crisp X syndrome, palpebral fissure syndrome (BPES), galactohyperglycemia, and carbohydrate deficiency Glycoprotein syndrome I, Perrault syndrome (PS) and so on. The pathogenetic genes of patients with Perrault syndrome, including HARS2, LARS2, C10ORF2, CLPP, and other patients with sensorineural deafness, were found in the Perrault syndrome by sequencing of the exon group. The female patients were accompanied by typical primary ovarian dysfunction. The whole exon group was sequenced and the other members of the family were sequenced in order to find a new POI pathogenic gene. Methods: the whole exon group was sequenced by Agilent SureSelect Human All Exon.V5 technique, and all the single base changes, insertion / deletion and public database were detected. The non synonymous mutation of the amino acid changes was detected and the candidate loci were screened according to the Mendel's law of heredity. Finally, the gene was screened according to the autosomal recessive way, and the common homozygous mutation site was screened in the patients. A missense mutation at the c.1388GA (p.R463Q) site of the C10ORF2 gene, which belongs to a new missense mutation that changes the amino acid from arginine to glutamine. The patient is a homozygous mutation and occurs in the line of the helicase of the.C10ORF2 gene of the encoded protein region of the protein. The replication of particles is essential. It is speculated that the changes in protein function caused by this mutation affect the mitochondrial function of the cells and lead to the occurrence of Perrault syndrome. Conclusion: the new missense mutation loci have been found in the spin region of the C10ORF2 gene by exons sequencing technology, and the discovery of the mutation is from the function of mitochondria. Research on the mechanism of POI provides a new direction. Second the mechanism of C10ORF2 gene in primary ovarian dysfunction. Objective: in the family of patients with sensorineural deafness (PS) with primary ovarian dysfunction, we found the missense mutation site c.1388 located on the C10ORF2 gene by the exon sequencing. GA (p.R463Q). In the previous study, it was found that the other amino acid changes at the same site resulted in the severe manifestation of the cerebellar cerebellar dysplasia in the infant. The.C10ORF2 gene encoded DNA helicase was involved in the process of mitochondrial replication in eukaryotic cells, and the mitochondria were regulated by the rich organelles in the granulosa and oocytes. The metabolism, cell cycle and signal transduction of granulosa cells and oocytes, but the relationship between the function of the gene and the ovary is not yet reported. This topic is to explore the pathogenesis of POI by C10ORF2 gene mutation. Method: by collecting the patients with Perrault syndrome. In the peripheral blood of the family, the peripheral blood DNA was extracted and the immortalized lymphocyte line of the C100RF2 gene c.1388GA (p.R463Q) mutation was established. The mitochondrial ATP production in the peripheral blood immortalized cells, the mitochondrial copy number and the formation of intracellular ROS were detected. The mitochondrial function changes caused by the mutation of the C10ORF2 gene were studied. The results were as follows: By extracting the peripheral blood of the patients and constructing immortalized lymphocytes, we found that the C10ORF2 gene mutation leads to the decrease of ATP in the cells and the increase of the ROS level, and the number of mitochondrial copies in the immortalized lymphocyte of the C10ORF2 gene mutation is obviously lower than that of the normal person. The changes seriously affect the activity of mitochondria in the cells and the level of oxidative phosphorylation, resulting in mitochondrial dysfunction. Conclusion: in the C10ORF2 gene, the c.1388GA (p.R463Q) mutation seriously affects the mitochondrial function of the cells. If this mutation occurs in the ovary, it will impede the normal energy metabolism of oocytes and granulosa cells in the egg nests. If the mitochondrial function is seriously defective, if the mitochondrial function is seriously defective, the decrease of ATP formation and the accumulation of ROS will lead to the death of the oocyte which can not be compensable. Therefore, the metabolic disorder in the mitochondria within the ovary caused by the C10ORF2 gene mutation may be one of the important mechanisms leading to the POI. The second chapter of the HELQ gene is in the original. Analysis of mutations in patients with ovarian dysfunction: the etiology of primary ovarian insufficiency (POI) is highly heterogeneous, and the cause of most patients is not yet clear. We found that POI, natural menopause age and premenopausal age have common genetic susceptibility, providing a new direction for the study of POI. Genomic association analysis found 13 sites associated with menopause age. In the subsequent bioinformatics analysis, 8 candidate genes were found to be associated with DNA damage repair. The HELQ gene had a high POI risk, so it was listed as an important candidate for POI. It encodes a protein HEL308, a DNA dependent ATP enzyme and DNA solution. The reparation of the interchain crosslinking reaction of DNA is involved with the RAD51 homologous protein. The repair of interchain crosslinking reaction requires the joint synergy of the S phase checkpoint of the cell division interval and the Vankoni anemia pathway to reduce the fertility of the.Helq-/- knockout mice, and the ovarian tissue section presents a obvious atrophy. The purpose of this study is to determine the mutation of the gene in the HELQ gene of the Han POI patients, and to provide a theoretical basis for the study of POI etiology and the guidance of clinical genetic counseling and reproductive guidance. Methods: to select 192 cases of POI patients of Han Chinese in the affiliated reproductive Hospital of Shandong University from 2012 to 2014. After the blood DNA was extracted, all the exons and exons of the HELQ gene were sequenced and the adjacent parts of the intron were sequenced. The results were compared with the normal population of the northern Han population in the database of China, and the genotype and allele frequencies of the SNP loci were analyzed by SPSS software. The results showed that 6 mononuclear nuclei were found in the exon sequencing of the HELQ gene. The two loci of rs1494961 and rs2047210 were statistically analyzed, and the genotype and allele frequencies were not statistically different from those of the control group. Rs13141136, rs7665103, rs11099600 and rs12645412 were statistically different from those of the control population, but they were synonymous changes. The coding sequence of HELQ gene is screened in patients with ovarian insufficiency, and the mutation of HELQ gene is not a common cause of primary ovarian insufficiency. Third the mutation analysis of the PRIM1 gene in the patients with primary ovarian insufficiency and the study of the gene knockout mice, the first part of the PRIM1 base in the patients with primary ovarian insufficiency Variable analysis objective: in recent years, more and more studies have found common genetic susceptibility between primary ovarian dysfunction and premenopause, which provides a new direction for exploring the pathogenesis of POI. A total of 13 sites associated with menopause age were found through the whole genome association analysis, including the PRIM1 gene.PRIM. The gene is not only closely related to the natural menopause age, and subsequent studies in the European population have found that the non synonymous polymorphic loci of the PRIM1 gene, rs2277339, and the early menopause and POI also have significant correlation with the.PRIM1 gene encoded DNA priming enzymes involved in the DNA replication process, and the synthesis of RNA primers to complete D by promoting the synthesis of RNA primers in the synthesis of kazaki fragments NA synthesis. The purpose of this study was to determine whether the mutation of the gene could lead to the occurrence of POI by measuring the PRIM1 coding sequence of 192 cases of POI patients in the Han nationality of China. Methods: 192 cases of POI patients who were diagnosed in the affiliated reproductive Hospital of Shandong University from 2014 to 2015 were selected as the research object, and the PRIM1 gene encoding was encoded by direct sequencing technology. The regional sequencing is the gene mutation screening, the results were compared with the normal Chinese northern population in the Ensemble database, and the genotype and allele frequencies of the SNP loci were statistically analyzed with SPSS software. Results: 3 known SNP loci rs2277339, rs1131514 and rs1026565 were screened in POI patients, respectively. The genotype and allele frequencies of the exons 1, exon 10 and intron 6 were not statistically different between the POI and the control group. Conclusion: the PRIM1 gene mutation is not common in the patients with primary ovarian dysfunction in Han Chinese. Although the rs2277339 loci in the European population are associated with primary ovarian dysfunction, but in the European population, There is no significance in the Chinese Han POI women. It is possible that the role of ethnic differences or less samples of this study leads to the further study of the role of the.PRIM1 gene in the pathogenesis of POI. Second the objective of Fertility Analysis in Prim1 knockout mice: the genetic study of primary ovarian dysfunction requires not only genomics. The study provides a basis for finding new pathogenicity sites, and it is more necessary to explore the biological support of animal experiments in the process of POI pathogeny. Therefore, in order to assess the physiological role of the PRIMl gene in the body, we constructed a Prim1 gene knockout mouse to investigate whether the deletion of the gene affects mice. Growth and reproduction function. Methods: CRISPR/Cas9 technique was used to find the Cas9 point of the target gene, design and construct the corresponding gRNA sequence. After testing its nucleic acid endonuclease activity, the mouse single cell embryo was injected with Cas9-mRNA, and the F1 generation heterozygote Prim1+/- mouse was obtained after breeding. The subgeneration subalgebra and the progeny genotypes were recorded by the cage. The effect of Prim1 gene deletion on the reproductive system in mice. Results: no homozygote Primr1-/- mice were born after Prim1+/- mice were caged. In the study of heterozygote Prim1+/- mice, the subalgebra, the size of the ovary and the number of oocytes at all levels in the ovary There was no significant difference in the birth type mice. Conclusion: there was no significant difference in fertility between the Prim1+/- mice and the wild type mice. No Prim1 homozygote offspring was born, indicating that the deletion of the gene may seriously affect the cell cycle and the process of DNA damage repair and lead to the apoptosis of the cells, causing the death of the Prim1-/- mouse embryo in the future. In the study, conditional Prim1 knockout mice could be considered to study the effect of the gene on ovarian function.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R711.75

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