Hedgehog信号通路与脊柱侧凸的遗传学病因研究

发布时间：2018-01-08 19:32

本文关键词：Hedgehog信号通路与脊柱侧凸的遗传学病因研究　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

更多相关文章： 脊柱侧凸 Hedgehog信号通路 遗传学

【摘要】：研究背景脊柱侧凸是指患者在站立位下,冠状位侧方弯曲超过10°的三维畸形,是临床中最为常见和复杂的畸形,不仅因为其致畸致残率高,手术难度大,更有大量患者伴随有其他畸形而给临床诊断和治疗造成困难。研究与脊柱侧凸相关的综合征是理解和认识脊柱畸形致病机理的重要手段。通过既往的探索和发现提示Hedgehog通路与可能与脊柱畸形以及与脊柱畸形伴随的其他畸形共同相关,但仍存在着许多未解决的问题:1、由于缺乏大规模脊柱畸形队列研究,对于脊柱畸形和其他伴随畸形的潜在相关性仍不十分清楚;2、既往的文献较少报道Hedgehog通路基因致病导致的脊柱畸形报道,或缺乏专业性的描述,为脊柱畸形的机制研究带来许多困难;3、关于Hedgehog通路相关基因,近年来既有与先天性脊柱侧凸的报道,又有与特发性脊柱侧凸的报道,两者是否有内在关联仍不清楚。因此,我们将试图通过遗传学角度,对Hedgehog通路基因在脊柱侧凸中扮演的角色进行进一步探讨和研究。研究目的和方法:1、通过大规模脊柱侧凸临床队列,寻找脊柱侧凸,特别是先天性脊柱侧凸与其伴随畸形的潜在相关性;2、通过外显子捕获测序技术,收集和设计以Hedgehog通路相关基因为主的捕获芯片,尝试发掘和明确Hedgehog信号通路基因突变对先天性脊柱侧凸人群的贡献率,并进行必要的基因型-表型分析。3、基于前期对Hedgehog通路相关基因AKAP2在特发性脊柱侧凸中的报道,验证大规模汉族特发性脊柱侧凸人群中AKAP2基因突变的贡献。研究结果:1、在356例先天性脊柱侧凸患者中,56.5%的患者伴随有其他系统畸形。其中以脊髓/神经管畸形最为多见,心脏畸形次之。与单纯CS相比,合并有其他畸形的患者脊柱畸形的表型更为复杂,受累节段更多。2、伴随或单纯伴随有心脏畸形患者,其脊柱在下胸段受累更为常见,与单纯CS的患者相比,具有明确的统计学差异。3、通过设计Hedgehog通路相关基因捕获芯片,在285例CS患者中进行测序分析,发现12例患者携带有高致病性Hedgehog通路相关基因突变。4、通过进一步的生物信息学分析与既往文献报道,认为PTCH2 p.R525Q,p.I1028T;PTCH1 p.V1094M 以及GLI3 p.P1093L,p.R863C 错义突变可能是患者的侧凸及伴随的多发畸形的致病基因,上述患者的脊柱畸形表现具有一定的共同点。5、对125例特发性脊柱侧凸患者进行AKAP2基因Sanger测序,发现一例患者携带rs765223801突变可能是其致病基因。该患者除脊柱侧凸外还伴有室间隔缺损。研究结论:1、脊柱侧凸常与其他系统畸形共同出现,且脊柱畸形与其他系统畸形可存在一定的相关性。2、Hedgehog通路相关基因突变可能在脊柱侧凸(包括CS和IS)及其他多系统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.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R682.3

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