我国儿科希特林缺陷病患者分子诊断研究：SLC25A13基因突变谱及其地理分布
发布时间：2018-08-09 09:23
【摘要】：目的:希特林缺陷病(Citrin Deficiency,CD)是由SLC25A13双等位基因突变导致的常染色体隐性遗传病,而希特林缺陷导致的新生儿肝内胆汁淤积症(Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency,NICCD)是目前最主要的儿科CD表型,其确诊依赖SLC25A13基因突变分析。目前我国人群的SLC25A13基因突变特征尚未被充分认识,还有大量CD患者被漏诊或误诊。本研究旨在研究我国SLC25A13基因突变谱及其地理分布特征,为不同区域CD患者的确诊提供相应的分子靶标。对象和方法:研究对象包括2013年3月初至2017年3月底我院儿科就诊的304位高度疑诊NICCD的患者及其父母;以及2005年至2013年2月底我院儿科已确诊的119位NICCD患儿及其父母。本研究以外周血为标本来源,利用PCR-RFLP/LA-PCR、Sanger测序、c DNA克隆和Western Blot分析等技术,开展NICCD分子诊断研究,并总结这12年来诊断的所有CD患者的SLC25A13基因突变谱。然后,以长江为界,将我国分南方、中部和北方三个区域,利用统计学SPSS17.0软件卡方检验分析比较不同区域间的突变分布特征和等位基因异质性。结果:(1)本研究确诊新CD患者204位,发现SLC25A13新突变类型7种,即c.755-1GC(p.252fs269X)、c.1381GT(p.E461X)、c.845_c.848+1del G(p.D283fs X285)、c.493CT(p.Q165X)、c.933_c.933+1ins GCAG(p.A312fs X317)、c.1706_1707del TA(p.S331fs X363)和[c.329-154_c.468+2352del2646;c.468+2392_c.468+2393ins23](p.E110fs127X)。(2)截止2017年3月底,课题组共确诊323位CD患者,其SLC25A13基因突变谱包含44种突变类型,其中有14种错义突变,7种缺失突变,12种无义突变,4种剪接突变,3种插入突变,1种重复突变,1种致病性SNP,1种异常剪接和1种复杂突变。(3)突变c.475CT(p.Q159X)、c.775CT(p.Q259X)、c.851_854del4、c.1078CT(p.R360X)、IVS11+1GA、c.1364GT(p.R455L)、c.1399CT(p.R467X)和IVS16ins3kb在我国不同区域之间的地理分布差异在统计学上具有显著性意义(P0.05)。(4)在58种SLC25A13基因型中,c.851_854del4/c.851_854del4、c.851_854del4/IVS16ins3kb、c.851_854del4/c.1399CT(p.R467X)和IVS16ins3kb/IVS11+1GA四种基因型的频率在各地区之间的差异有显著性意义(P0.05)。(5)北方人群SLC25A13等位基因异质性高于南方地区。结论:本研究通过传统DNA分析方法结合cDNA克隆和Western Blot分析等分子诊断技术,共诊断了204位新的CD患者,同时发现了7种新的致病性突变,扩展了SLC25A13基因突变谱。课题组目前共诊断CD患者323名,建立了国内外文献中最大的CD患者队列,其丰富的SLC25A13基因突变谱和独特的地理分布特征为后续NICCD分子诊断提供了可靠依据,同时为我国不同区域CD患者分子诊断靶标的确定提供了科学依据。
[Abstract]:Objective: Khitrin deficiency disease (Citrin defect CD) is an autosomal recessive disease caused by SLC25A13 double allele mutation, and (Neonatal Intrahepatic Cholestasis caused by Citrin deficiency of neonatal intrahepatic cholestasis caused by Khitrin deficiency is the most important pediatric CD phenotype. Its diagnosis depends on SLC25A13 gene mutation analysis. At present, the characteristics of SLC25A13 gene mutation in Chinese population have not been fully recognized, and a large number of patients with CD have been missed or misdiagnosed. The purpose of this study was to study the SLC25A13 gene mutation profile and its geographical distribution in China, and to provide molecular targets for the diagnosis of CD patients in different regions. Participants and methods: the subjects included 304 pediatric patients with suspected NICCD and their parents from March 2013 to the end of March 2017, and 119 children with NICCD and their parents who had been diagnosed in pediatrics from 2005 to February 2013. In this study, we used PCR-RFLP / LA-PCRGR Sanger sequencing DNA cloning and Western Blot analysis to study the molecular diagnosis of NICCD, and summarized the SLC25A13 gene mutation profiles of all CD patients diagnosed in the past 12 years. Then, taking the Yangtze River as the boundary, China is divided into three regions: south, middle and north, and the mutation distribution and allelic heterogeneity among different regions are analyzed and compared by statistical SPSS17.0 software chi-square test. 缁撴灉:(1)鏈爺绌剁‘璇婃柊CD鎮ｈ，
本文编号：2173649
[Abstract]:Objective: Khitrin deficiency disease (Citrin defect CD) is an autosomal recessive disease caused by SLC25A13 double allele mutation, and (Neonatal Intrahepatic Cholestasis caused by Citrin deficiency of neonatal intrahepatic cholestasis caused by Khitrin deficiency is the most important pediatric CD phenotype. Its diagnosis depends on SLC25A13 gene mutation analysis. At present, the characteristics of SLC25A13 gene mutation in Chinese population have not been fully recognized, and a large number of patients with CD have been missed or misdiagnosed. The purpose of this study was to study the SLC25A13 gene mutation profile and its geographical distribution in China, and to provide molecular targets for the diagnosis of CD patients in different regions. Participants and methods: the subjects included 304 pediatric patients with suspected NICCD and their parents from March 2013 to the end of March 2017, and 119 children with NICCD and their parents who had been diagnosed in pediatrics from 2005 to February 2013. In this study, we used PCR-RFLP / LA-PCRGR Sanger sequencing DNA cloning and Western Blot analysis to study the molecular diagnosis of NICCD, and summarized the SLC25A13 gene mutation profiles of all CD patients diagnosed in the past 12 years. Then, taking the Yangtze River as the boundary, China is divided into three regions: south, middle and north, and the mutation distribution and allelic heterogeneity among different regions are analyzed and compared by statistical SPSS17.0 software chi-square test. 缁撴灉:(1)鏈爺绌剁‘璇婃柊CD鎮ｈ，
本文编号：2173649
本文链接：https://www.wllwen.com/kejilunwen/jiyingongcheng/2173649.html
最近更新
教材专著
