CFTR基因新发突变在中国儿童囊性纤维化中的致病性和分子机制研究

Cystic fibrosis (CF) is one type of life-threatening autosomal recessive disease, resulting from genetic mutations located on chromosome 7q31.2, which codes for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR). CF was considered to be extremely rare among the Chinese population. Only 34 CF cases with Chinese origin have been reported during the 40-year period from 1974 to 2014, and no epidemiological data on the prevalence of the disease is available. Currently, 35 pediatric cases from mainland China have been clinically diagnosed in our center. The profiles of CFTR mutations vary greatly among different populations based on their geographical and ethnic origins, and there is intense association of prognosis with the diagnostic timing. Therefore, there is an urgent need to understand the genotyping and pathogenic mechanism of the CFTR mutations in Chinese patients. Here, we characterize the mutational spectrum of the CFTR gene in Chinese CF children, to investigate the relationship of genotype and clinical phenotype. Moreover, the functional analysis will be used to interpret pathogenicity and molecular mechanism of CFTR Novel Mutations. The purposes of this study was to establish a reliable functional analysis system at molecular level, which would greatly contributes to prevention, diagnosis, and even precise therapy of the disease.

囊性纤维化（CF）是由编码囊性纤维化跨膜转录调节因子（CFTR）蛋白的第7号常染色体基因突变引起的致死性隐性遗传病。此病在中国人中极其罕见，在1974-2014的40年里，全世界报道的华人病例仅34例，且我国尚无CF整体发病情况的流行病学统计数据。目前我们已经收集了35例中国大陆地区的CF临床诊断病例。CFTR基因突变在不同种族、地理间的差异性极大，且此病的预后与诊疗时机密切相关，故对中国人CFTR突变及其致病机制的研究迫在眉睫。鉴于此，本课题通过鉴定中国CF患儿CFTR基因突变，探讨基因型与临床表型之间的关联，并在此基础上建立野生型及突变型CFTR真核表达载体及过表达细胞模型，阐明新发突变在中国人CF疾病中的致病性和分子机制。本课题的完成可获得CFTR基因在中国患儿中的突变谱，并在分子水平上建立系统的功能分析体系，对CF疾病的预防、诊断及精准治疗都有重要的临床意义。

囊性纤维化（CF）是由编码囊性纤维化跨膜转录调节因子（CFTR）蛋白的第7号常染色体基因突变引起的致死性隐性遗传病。既往认为此病在中国人种中极其罕见，然而随着对CF疾病认识程度的加深及在全国最先开展汗液氯离子测定技术之后，本课题组已经收集了69例中国大陆地区的CF临床诊断病例，其样本量相当于过去40年全世界报道的华人病例总和的2倍。课题研究发现我国患儿的临床表型及基因型均与欧美高加索人存在极大差异，对疾病的认识不足及诊断方法的局限可能是误诊或漏诊此病的最大障碍。通过对CFTR基因的突变检测，我们共发现76种不同的突变，其中新发突变共39种，既往均无文献报道。针对11种致病性不明的新发错义突变，本课题组成功建立了CFTR真核表达载体及过表达细胞模型，研究发现CFTR突变通过影响其编码蛋白的合成、转运，氯通道开放性以及自噬活性，导致疾病的发生发展。其中重型突变可能影响其编码蛋白的合成、转运，轻型突变可能仅影响其氯通道开放性。本课题的完成可获得CFTR基因在中国患儿中的突变谱，并在分子水平上建立系统的功能分析体系，对CF疾病的预防、诊断及精准治疗都有重要的临床意义。

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