本文關(guān)鍵詞：Hedgehog信號(hào)通路與脊柱側(cè)凸的遺傳學(xué)病因研究　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

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【摘要】：研究背景脊柱側(cè)凸是指患者在站立位下,冠狀位側(cè)方彎曲超過(guò)10°的三維畸形,是臨床中最為常見(jiàn)和復(fù)雜的畸形,不僅因?yàn)槠渲禄職埪矢?手術(shù)難度大,更有大量患者伴隨有其他畸形而給臨床診斷和治療造成困難。研究與脊柱側(cè)凸相關(guān)的綜合征是理解和認(rèn)識(shí)脊柱畸形致病機(jī)理的重要手段。通過(guò)既往的探索和發(fā)現(xiàn)提示Hedgehog通路與可能與脊柱畸形以及與脊柱畸形伴隨的其他畸形共同相關(guān),但仍存在著許多未解決的問(wèn)題:1、由于缺乏大規(guī)模脊柱畸形隊(duì)列研究,對(duì)于脊柱畸形和其他伴隨畸形的潛在相關(guān)性仍不十分清楚;2、既往的文獻(xiàn)較少報(bào)道Hedgehog通路基因致病導(dǎo)致的脊柱畸形報(bào)道,或缺乏專業(yè)性的描述,為脊柱畸形的機(jī)制研究帶來(lái)許多困難;3、關(guān)于Hedgehog通路相關(guān)基因,近年來(lái)既有與先天性脊柱側(cè)凸的報(bào)道,又有與特發(fā)性脊柱側(cè)凸的報(bào)道,兩者是否有內(nèi)在關(guān)聯(lián)仍不清楚。因此,我們將試圖通過(guò)遺傳學(xué)角度,對(duì)Hedgehog通路基因在脊柱側(cè)凸中扮演的角色進(jìn)行進(jìn)一步探討和研究。研究目的和方法:1、通過(guò)大規(guī)模脊柱側(cè)凸臨床隊(duì)列,尋找脊柱側(cè)凸,特別是先天性脊柱側(cè)凸與其伴隨畸形的潛在相關(guān)性;2、通過(guò)外顯子捕獲測(cè)序技術(shù),收集和設(shè)計(jì)以Hedgehog通路相關(guān)基因?yàn)橹鞯牟东@芯片,嘗試發(fā)掘和明確Hedgehog信號(hào)通路基因突變對(duì)先天性脊柱側(cè)凸人群的貢獻(xiàn)率,并進(jìn)行必要的基因型-表型分析。3、基于前期對(duì)Hedgehog通路相關(guān)基因AKAP2在特發(fā)性脊柱側(cè)凸中的報(bào)道,驗(yàn)證大規(guī)模漢族特發(fā)性脊柱側(cè)凸人群中AKAP2基因突變的貢獻(xiàn)。研究結(jié)果:1、在356例先天性脊柱側(cè)凸患者中,56.5%的患者伴隨有其他系統(tǒng)畸形。其中以脊髓/神經(jīng)管畸形最為多見(jiàn),心臟畸形次之。與單純CS相比,合并有其他畸形的患者脊柱畸形的表型更為復(fù)雜,受累節(jié)段更多。2、伴隨或單純伴隨有心臟畸形患者,其脊柱在下胸段受累更為常見(jiàn),與單純CS的患者相比,具有明確的統(tǒng)計(jì)學(xué)差異。3、通過(guò)設(shè)計(jì)Hedgehog通路相關(guān)基因捕獲芯片,在285例CS患者中進(jìn)行測(cè)序分析,發(fā)現(xiàn)12例患者攜帶有高致病性Hedgehog通路相關(guān)基因突變。4、通過(guò)進(jìn)一步的生物信息學(xué)分析與既往文獻(xiàn)報(bào)道,認(rèn)為PTCH2 p.R525Q,p.I1028T;PTCH1 p.V1094M 以及GLI3 p.P1093L,p.R863C 錯(cuò)義突變可能是患者的側(cè)凸及伴隨的多發(fā)畸形的致病基因,上述患者的脊柱畸形表現(xiàn)具有一定的共同點(diǎn)。5、對(duì)125例特發(fā)性脊柱側(cè)凸患者進(jìn)行AKAP2基因Sanger測(cè)序,發(fā)現(xiàn)一例患者攜帶rs765223801突變可能是其致病基因。該患者除脊柱側(cè)凸外還伴有室間隔缺損。研究結(jié)論:1、脊柱側(cè)凸常與其他系統(tǒng)畸形共同出現(xiàn),且脊柱畸形與其他系統(tǒng)畸形可存在一定的相關(guān)性。2、Hedgehog通路相關(guān)基因突變可能在脊柱側(cè)凸(包括CS和IS)及其他多系統(tǒng)畸形中扮演重要作用。
[Abstract]:Backgroundscoliosis refers to patients in standing position, coronal lateral bending over 10 degree three-dimensional deformity, is the most common and complicated clinical abnormalities, not only because of its teratogenic high morbidity, difficult surgery, a large number of patients with other malformations caused difficulties for clinical diagnosis and treatment research on comprehensive. Syndrome associated with scoliosis is an important means of understanding the pathogenesis of spinal deformity. Hedgehog pathway and may be associated with spinal deformity and spinal deformity associated with other malformations by common related previous exploration and discovery, but there still exist many unsolved problems: 1, due to the lack of large-scale cohort study for spinal deformity. Spinal deformity and other abnormalities associated with potential is still not very clear; 2, the literature reported less pathogenic genes of the Hedgehog pathway leads to spinal deformity previously reported, or The lack of professional description, brings many difficulties for the research on the mechanism of spinal deformity; 3 genes on the Hedgehog pathway, in recent years with congenital scoliosis were reported, and with idiopathic scoliosis reports, whether the two are intrinsically related remains unclear. Because of this, we will attempt to use genetics point of view, further discussion and Study on the genes of the Hedgehog pathway plays in the scoliosis role. The research purpose and methods: 1, through large-scale scoliosis clinical cohort, for scoliosis, especially congenital scoliosis associated with potential malformation; 2 through exon trapping sequencing technology, chip collection and capture the design of Hedgehog pathway related genes in the attempt to explore and identify Hedgehog signaling pathway gene mutation of congenital scoliosis population contribution rate, and genotype necessary tables Analysis of.3, early on Hedgehog pathway related gene AKAP2 in idiopathic scoliosis is reported based on the verification of large-scale Han idiopathic scoliosis population AKAP2 gene mutation contribution. Results: 1, in 356 cases of congenital scoliosis patients, 56.5% patients with other malformations. Among them the spinal cord / neural tube malformation is the most common, heart malformation second. Compared with CS, with the phenotype of other abnormalities deformity is more complex, the affected segments with more.2, or only with patients with heart malformation, the spine in the lower thoracic involvement is more common, compared with the simple CS patients, with statistical difference.3 clear, capture chip through the design of Hedgehog pathway related genes, sequencing analysis in 285 patients with CS, 12 patients with highly pathogenic Hedgehog pathway related gene mutation by.4. Further bioinformatical analysis and literature reported that PTCH2, p.R525Q, p.I1028T; PTCH1 p.V1094M and GLI3 p.P1093L, p.R863C missense mutation in patients with scoliosis and multiple malformations with pathogenic gene, the spinal deformity patients with a common.5, 125 cases of patients with idiopathic scoliosis AKAP2 Sanger gene sequencing, one patient was found to carry rs765223801 mutation may be the pathogenic gene. The patients with scoliosis is associated with ventricular septal defect. Conclusions: 1, scoliosis often appear together with other malformations, and spinal deformity and other abnormalities may exist certain correlation between.2 system and Hedgehog pathway related genes mutation in scoliosis (including CS and IS) and other multi system play an important role of deformity.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R682.3

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