CC2D1A、CC2D2A、CRBN基因与秦巴山区精神发育迟滞的相关性研究
发布时间：2018-03-10 00:10
本文选题：精神发育迟滞 切入点：CC2D1A基因 出处：《西北大学》2012年博士论文 论文类型：学位论文
【摘要】：精神发育迟滞(mental retardation, MR)是一类常见的神经、精神类疾病,以智力低下和社会适应能力不足为主要特征,发病于18周岁之前。MR的致病原因较为复杂,包括遗传与环境两大类因素,其中约有2/3的病例具有遗传基础。秦巴山区是我国MR的高发地区之一,MR的总患病率约为2.70%,儿童患病率约为2.78%,是全国平均水平的2-3倍,给当地的社会经济文化发展带来极大的负担。因此,从遗传学的角度对秦巴山区MR的致病机制进行研究,是一项亟待持续、深入开展的有意义的工作。 由遗传因素所致的MR具有很高的遗传异质性,目前已发现许多基因或位点与之相关。由于MR患者以男性居多,故长期以来对该病的分子遗传学研究主要集中于X染色体,而对常染色体则很少涉及。然而,近期研究表明常染色体基因可能在智力或认知能力的遗传中发挥着重大作用,对秦巴山区患病家系的调查也表明当地很多MR家系符合常染色体隐性遗传的模式,因此本文选择了3个位于常染色体的MR候选基因(CC2D1A、 CC2D2A、CRBN)作为研究对象,来探讨这些基因与秦巴山区人群的MR之间是否具有相关性。 CC2D1A和CC2D2A基因所编码的蛋白质均通过其C2结构域参与Ca2+调控的信号通路,对神经可塑性与神经系统的发育产生影响；CRBN基因的蛋白质产物属于ATP依赖的Lon蛋白酶,可对中枢神经系统的多个信号通路进行调控。研究表明这3个基因的突变分别导致国外一些家系的非特异性MR(即除了智力低下及社会适应能力不足之外,没有其它临床体征的MR)。 为了避免传统的病例-对照样本可能存在人群层化而影响结果的准确性,本文以来自秦巴山区的172个MR核心家系作为样本,在上述3个基因内部一共选择了14个SNP位点作为遗传标记,进行关联研究。据我们所知,这也是第一次对这3个基因与MR之间的关系进行以基于家系的随机人群为对象的关联分析。基因分型采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)和PCR-单链构象多态性(PCR-SSCP)法(结合DNA测序)。等位基因频率和基因型频率、哈代-温伯格平衡检验、单位点分析、连锁不平衡(LD)分析和单倍型构建、单倍型分析、统计效力计算分别应用SPSS15.0、Haploview3.2、UNPHASED3.1.3、Epilnfo3.5.1和Quanto1.2.4等软件进行。 研究结果如下： 1.在CC2D1A基因中选择了rs6511898、rs6511901和rs10410239等3个SNP标记,单位点分析结果表明,这些单个标记位点均与MR没有关联(P0.05)；但由rs6511901和rs10410239所构成的单倍型区域则具有极其显著的传递不平衡(P=0.0009),其中单倍型T-C较多地传递给患者(P=0.0238),而T-T则较少被传递(P=0.0016)。 2.在CC2D2A基因中选择了rs7664843、rs1861044、rs10025837、rs13116304和rs7661102等5个SNP标记,单位点分析结果均为阴性(P0.05)。LD分析表明这5个SNP标记分别构成两个单倍型块,由rs7664843和rs1861044所组成的单倍型块Ⅰ与MR无关(P0.05),而由rs10025837、rs13116304和rs7661102构成的单倍型块Ⅱ则与MR显著相关(P=0.0004),其中单倍型C-C-A更多地传递给患者(P=0.0486),而C-C-G较少传递(P=0.0026)。以上结果在经过Bonferroni校正后仍具有一定的显著性。 3.在CRBN基因中选择了rs711613、s1669322、rs1672761、rs1669336、rs17027638和rs16693426等6个SNP标记,这些标记中仅有rs1669322的单位点分析结果显示出相关性(P=0.0371),但在校正后不再具有阳性趋势。LD分析表明rs1669336、 rs17027638和rs1669342构成一个单倍型区域,该区域的传递与MR表型无关(总P值及各种特殊单倍型的P值均0.05)。 根据以上结果,本研究认为CC2D1A、CC2D2A基因与秦巴山区人群的MR发病机制之间存在相关性,并且某些特殊的单倍型可能有着易感性或保护作用。CC2D1A基因中呈传递不平衡的单倍型块(rs6511901-rs10410239)与基因的重要功能区相邻,可能在该单倍型块附近有某个与MR患病风险相关且多态性极低的位点,导致单倍型分析出现显著的传递不平衡；CC2D2A基因的单倍型块Ⅱ覆盖了该基因的重要功能区以及在国外家系中发现的突变位点,可能在其内部也存在一个与MR表型关联且变异频率很低的位点。另外,我们目前也不能排除组成单倍型的各个位点之间存在某种相互作用而对人群易感性产生影响的可能。对于CRBN基因,由于其单位点分析和单倍型分析结果均为阴性或在校正之后为阴性,因此我们认为该基因与秦巴山区人群的MR发病风险之间不存在明显的相关性。最后,考虑到MR具有很高的遗传异质性,上述所有结论尚需以更多和更加深入的探索来进行验证。
[Abstract]:Mental retardation (mental retardation MR) is a kind of common neurological, mental diseases, with mental retardation and lack of ability to adapt to society as the main features, causes of onset before the age of 18 in.MR is more complex, including genetic and environmental factors in two categories, of which about 2/3 cases with the genetic basis of Qin. Ba mountain is one of the regions with a high incidence of MR in China, the prevalence of MR is about 2.70%, the prevalence rate of about 2.78% children, is 2-3 times the national average, bring great burden to the local social economic and cultural development. Therefore, to study the pathogenic mechanism of Qinba mountain MR from the genetic perspective that is an urgent need to continue in-depth meaningful work.
By genetic factors induced by MR with genetic heterogeneity is very high, it has been found that many genes or loci associated with MR patients. Due to males, so long in molecular genetics of the disease mainly focused on the X chromosome, and pairs of autosomes are rarely involved. However, recent studies show that autosomal the gene may play an important role in genetic intelligence or cognitive ability in the investigation of families in the Qinba mountain area also shows that many of the local MR family with autosomal recessive pattern, this paper chose 3 in chromosomal MR candidate genes in the body (CC2D1A, CC2D2A, CRBN) as the research object. To investigate whether there is any correlation between these genes and Qinba Mountain populations of MR.
CC2D1A and CC2D2A gene encoding protein signaling through its C2 domain is involved in the regulation of Ca2+, the influence on neural plasticity and neural development; the protein product of CRBN gene belongs to the ATP dependent Lon protease, can control a plurality of signal pathways in the central nervous system. The research showed that nonspecific MR the mutations in 3 genes lead to some foreign families (that is, in addition to mental retardation and lack of ability to adapt to society, there is no other clinical signs of MR).
In order to avoid the traditional case-control sample accuracy possible population stratification and influence the results, based on the 172 MR nuclear families from Qinba mountain area as a sample, within the 3 genes choose a total of 14 SNP loci as genetic markers for association study. To our knowledge, this is the first the relationship between these 3 genes and MR in random population based on pedigree analysis object of the association. Genotyping by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and PCR- single strand conformation polymorphism (PCR-SSCP) method (with DNA sequencing). Allele frequencies and gene frequency, Hardy Weinberg equilibrium test, unit analysis, linkage disequilibrium (LD) construction, analysis and haplotype analysis, statistical power calculations were used to SPSS15.0, Haploview3.2, UNPHASED3.1.3, Epilnfo3.5.1 and Quanto1.2 .4 and other software.
The results of the study are as follows:
1.鍦–C2D1A鍩哄洜涓，
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