原发性纤毛运动障碍纤毛超微结构与基因型分析

发布时间：2018-03-18 17:05

本文选题：原发性纤毛运动障碍　切入点：Kartagener综合征　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景:原发性纤毛运动障碍(PCD)是纤毛结构缺陷和(或)运动障碍造成纤毛黏液清除能力降低或丧失的罕见遗传性疾病,遗传方式大多为常染色体隐性遗传,少数为常染色体显性遗传和X染色体连锁遗传,另有部分遗传方式未明。纤毛结构和(或)功能缺陷是PCD发病主要原因,与其发病相关的"9+2"结构运动纤毛主要分布于上下呼吸道、耳咽管、室管膜、输卵管、精子鞭毛等处,受累器官决定PCD临床症状,主要表现为慢性鼻-鼻窦炎、渗出性中耳炎、反复呼吸道感染、支气管扩张,可伴男性不育、女性生育能力降低等,其中约50%合并内脏转位称为Kartagener综合征。PCD辅助检查多种多样,包括鼻呼出气一氧化氮、影像学检查、高速数字视频成像、透射电子显微镜、基因检测等,但都有其不可避免的缺陷,目前尚无诊断"金标准"。基因检测联合其他检查有助于PCD的早期和精确诊断,PCD纤毛结构缺陷类型与其基因突变型相关。有关PCD致病基因的研究多在欧美白种人中进行,我国PCD患者的分子遗传特点是否与西方国家存在差异尚不明确。目的:探讨原发性纤毛运动障碍纤毛超微结构缺陷及基因突变特点,分析其基因型-纤毛结构表型关联性。方法:对山东省立医院儿科2013年-2016年通过支气管粘膜活检电镜诊断的4例PCD患儿采用靶向目标捕获结合二代测序,分析其临床表现、纤毛超微结构和基因突变特点。通过关键词"PCD、gene、chinese"分别检索在线人类孟德尔遗传数据库(OMIM)、人类基因突变数据库(HGMD)、Pubmed和中国知网(CNKI)上报道的中国PCD患者基因突变的相关资料,总结其基因突变和纤毛结构的关系。结果:(1)4例患儿年龄3-11岁,3女1男,均有反复呼吸道感染、慢性鼻-鼻窦炎;2例伴全内脏转位;4例胸部高分辨率CT均有支气管扩张,其中1例伴有弥漫性泛细支气管炎征象。(2)纤毛超微结构2例为内外动力臂缺失,2例为微管数目异常+内动力臂缺陷;3例发现PCD相关基因突变,分别为LRRC6基因复合杂合突变、DNAH5及DNAH11杂合突变、CCDC39基因纯和突变,]例未发现已知PCD相关致病基因变异,例3患儿胞姐有反复呼吸道感染、慢性鼻-鼻窦炎症状,基因验证同为CCDC39纯和突变。以上突变位点均为未报道的新突变。(3)我国关于PCD致病基因的研究病例集中在Kartagener综合征患者,共7例基因检测阳性患者中,6例为Kartagener综合征,其基因型-结构表型关联性与以往报道基本相符。结论:对于自幼反复呼吸道感染,反复咳喘治疗效果不佳者,胸部影像学表现为支气管扩张或细支管炎的患者,注意鉴别PCD。PCD纤毛结构及运动障碍与其基因突变类型相关,基因检测联合其他辅助检查有助于PCD的早期和精确诊断。通过先证者的基因诊断,明确其遗传病因,对于PCD患者家庭遗传咨询及产前诊断具有指导意义。
[Abstract]:Background: primary ciliated dyskinesia (PCD) is a rare hereditary disease caused by ciliated structural defects and / or dyskinesia, which decreases or loses the mucus clearance ability of ciliates. Most of the genetic patterns are autosomal recessive inheritance. A few were autosomal dominant inheritance and X chromosome linkage inheritance, and some of the genetic patterns were unknown. Ciliated structure and / or functional defects were the main causes of PCD. The motility cilium of "9.2" structure associated with the disease was mainly distributed in the upper and lower respiratory tract, otopharynx tube, ependyma, fallopian tube, sperm flagella, etc. The clinical symptoms of PCD were determined by the involved organs, which were mainly characterized by chronic rhinosinusitis and effusion otitis media. Recurrent respiratory tract infection, bronchiectasis, male infertility, and decreased fertility in women, among them, about 50% patients with visceral transposition called Kartagener syndrome. PCD adjuvant examinations include nasal exhalation nitric oxide, imaging examination, and so on. High-speed digital video imaging, transmission electron microscopy, gene detection and so on, but all have their inevitable defects, At present, there is no diagnostic "gold standard". Gene detection combined with other tests is helpful to the early and accurate diagnosis of PCD ciliated structural defects associated with its gene mutation. The study of PCD pathogenic genes is mostly carried out in Caucasians in Europe and America. It is not clear whether the molecular genetic characteristics of PCD patients in China are different from those in western countries. Objective: to investigate the ultrastructural defects and gene mutation characteristics of cilia in patients with primary ciliate dyskinesia. Methods: from 2013 to 2016, four cases of PCD diagnosed by electron microscope of bronchial mucosa biopsy were analyzed by targeting target capture combined with second-generation sequencing, and their clinical manifestations were analyzed. Cilium ultrastructure and gene mutation characteristics. The relevant data of gene mutations in Chinese PCD patients reported in online human Mendelian genetic database (OMIM), human gene mutation database (PCD) Pubmed and CNKI were searched by using the key word "PCD gene gene". Results there were 4 children aged 3-11 years with recurrent respiratory tract infection, 2 patients with chronic rhinosinusitis accompanied with total visceral transposition, 4 patients with bronchiectasis, and 4 patients with chronic rhinosinusitis accompanied with total visceral transposition. One case with diffuse panbronchiolitis.) the ultrastructure of cilium was found in 2 cases with loss of internal and external dynamic arm, 2 cases with abnormal number of microtubules, 3 cases with abnormal number of microtubules and 3 cases with PCD related gene mutation. LRRC6 gene combined heterozygous mutation (LRRC6 H5) and DNAH11 heterozygosity mutation (CCDC39) were pure and mutated respectively. There was no known mutation of PCD related pathogenic gene. In case 3, there was recurrent respiratory tract infection and chronic rhinosinusitis. All of the above mutation sites are new mutations, which are not reported. In our country, the study of PCD pathogenicity genes is concentrated in the patients with Kartagener syndrome, 6 out of 7 patients with positive gene test are Kartagener syndrome. Conclusion: for the young patients with recurrent respiratory tract infection and the treatment of repeated cough and asthma, the chest imaging findings were bronchiectasis or bronchitis. Attention should be paid to the identification of ciliated structure and dyskinesia of PCD.PCD associated with the type of gene mutation. Gene detection combined with other auxiliary examinations is helpful to the early and accurate diagnosis of PCD. The genetic cause of the disease can be identified by gene diagnosis of the proband. It has guiding significance for family genetic counseling and prenatal diagnosis of PCD patients.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.9

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