携带COL4A3或COL4A4基因突变的Ⅳ型胶原相关性肾病6个家系分析  

A retrospective analysis of six families diagnosed with collagen Ⅳ-related nephropathy carrying heterozygous COL4A3/COL4A4 mutation

作　　者：林芙君[1] 陆玮[1] 单剑萍[1] 朱淳[1] 邹军[1] 边帆[1] 吴萍[1] 管雯斌[2] 张翀[1] 蒋更如[1] LIN Fujun;LU Wei;SHAN Jianping;ZHU Chun;ZOU Jun;BIAN Fan;WU Ping;GUAN Wenbin;ZHANG Chong;JIANG Gengru(Renal Division, Department of Internal Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Chin)

机构地区：[1]上海交通大学医学院附属新华医院肾脏科,上海200092 [2]上海交通大学医学院附属新华医院病理科,上海200092

出　　处：《上海医学》2018年第2期104-109,共6页Shanghai Medical Journal

基　　金：国家自然科学基金青年项目(81500507);上海交通大学医学院附属新华医院优秀青年人才培养计划(2015001)

摘　　要：目的分析总结携带COL4A3或COL4A4基因突变的Ⅳ型胶原相关性肾病患者的临床表型和基因突变的特点,以提高对该疾病的认识。方法回顾性分析2013年1月—2017年9月于上海交通大学医学院附属新华医院肾脏科明确诊断携带COL4A3或COL4A4基因突变的6个Ⅳ型胶原相关性肾病家系的临床、病理表型和基因突变。基因检测方法为首先对6个家系的先证者进行全外显子组捕获-二代测序(包括COL4A3、COL4A4、COL4A5基因)并进行生物信息学分析,然后运用Sanger法对候选突变位点进行家系内验证。结果在6个家系中共发现19例患者携带COL4A3或COL4A4基因杂合突变,其中5例携带COL4A3基因杂合突变,14例携带COL4A4基因杂合突变(有2例同时携带2个COL4A4基因杂合突变)。共发现7种COL4A3或COL4A4基因突变且均为错义突变(6种为甘氨酸突变为其他氨基酸),其中6种突变之前未见报道。19例患者中,7例出现肾功能下降,其中4例进展至终末期肾脏病(ESRD)并有1例死亡,发生肾功能下降和ESRD的年龄分别为(42.6±10.3)和(53.0±6.9)岁;18例患者有肾性血尿;13例患者有不同程度蛋白尿(其中4例患者尿蛋白水平>3.0g/24h)。无患者合并耳聋和眼部病变。7例患者行肾活组织检查,光学显微镜下5例患者表现为局灶节段性肾小球硬化(FSGS),2例患者表现为系膜增生性改变(其中1例免疫荧光表现为IgA肾病)。电子显微镜下发现3例患者局部肾小球基底膜(GBM)变薄,无患者出现GBM致密层撕裂、分层等Alport综合征改变。7例患者α3、α5免疫荧光染色均未见异常。结论携带COL4A3或COL4A4基因突变的Ⅳ型胶原相关性肾病患者中发生肾功能损害和ESRD的并不少见,光学显微镜下多表现为FSGS,易被误诊为其他肾小球疾病。建议对疑似Ⅳ型胶原相关性肾病的患者进行COL4A3、COL4A4、COL4A5基因检测,进一步确诊,予早期干预治疗。Objective To retrospectively analyze the clinical and genetic characteristics of patients with collagen Ⅳ-related nephropathy carrying heterozygous COL4A3/OOL4A4 mutations. Methods Totally 19 patients from six families diagnosed with typeⅣ collagen nephropathy in Xinhua Hospital from January 2013 to September 2017 by means of clinical, pathological and genetic diagnosis were included in this study. Probands from each family were selected for the testing of whole exome sequencing （WES）. All variants detected by WES will be filtered through the stepwise filtering procedure to find the most likely causal variant. Candidate causal variants will be further validated by Sanger sequencing within the family and deleterious effect of co-segregated variants will be reviewed in genetic disease mutation database and predicted by in silico analysis as needed to finally pinpoint the causative mutation. Results Among 19 patients, five were detected to have COL4A3 heterozygous mutations and 15 with OOL4A4 heterozygous mutations （two of them carrying compound heterozygous COL4A4 mutations）. All the seven heterozygous COL4A3/COL4A4 mutations detected by WES were missense mutations, in which six were at glycine residues. Seven patients had renal function impairment, of whom 4 progressed into end-stage renal disease （ESRD） and one died. The patients suffered from renal function impairment and ESRD at （42.6 ± 10.3） years old and （53.0 ± 6.9） years old, respectively. There were 18 patients with hematuria, 13 patients with proteinuria （proteinuria 〉3.0 g/24 h in four patients）. No patients in this cohort had hearing loss or eye lesions. Renal biopsy was performed in seven patients, and five patients presented with focal segmental sclerosis （FSGS）whereas other two patients with mainly mesangial proliferation changes, Regional glomerular basement membrane （GBM） became thin in three patients. Alport syndrome was not found. The results of a3/a5 immuno-staining were normal. Conclusions It is not uncom

关 键 词：Ⅳ型胶原相关性肾病 遗传性肾脏疾病 COL4A3基因 COL4A4基因 二代测序 

分 类 号：R692[医药卫生—泌尿科学]