新UMOD基因突变:家族性青少年高尿酸血症肾病家系研究  

New UMOD gene mutation: a familial study of juvenile hyperuricemia nephropathy

作　　者：刘苑莹 王丹[1] 范瑾瑾[1] 陈文芳[1] 陈崴[1] 李志坚[1] 王欣[1] Liu Yuanying;Wang Dan;Fan Jinjin;Chen Wenfang;Chen Wei;Li Zhijian;Wang Xin(Department of Nephrology,the First Affiliated Hospital of Sun Yat-sen University,Key Laboratory of Nephrology,National Health Commission of China and Guangdong Province,Guangzhou 510080,China)

机构地区：[1]中山大学附属第一医院肾内科国家卫健委及广东省肾脏病重点实验室,广州510080

出　　处：《中华肾脏病杂志》2020年第10期737-743,共7页Chinese Journal of Nephrology

基　　金：国家卫生健康委员会重点实验室基金。

摘　　要：目的:通过对1个家族性青少年高尿酸血症肾病(familial juvenile hyperuricemic nephropathy,FJHN)患者家系进行临床、病理及基因检测分析,提高对该罕见疾病的认识。方法:收集FJHN先证者家系成员的临床资料,对先证者行肾组织常规病理检查,免疫荧光染色检测肾组织Uromodulin(UMOD)蛋白的表达。收集先证者及其亲属外周血,采用双链DNA探针基因捕获和高通量测序法检测包含UMOD在内的泌尿系统疾病相关基因。结果:先证者家系中受累个体共7人,遗传方式符合常染色体显性遗传。7例受累家族成员中1例3岁幼儿尚未发现任何临床指标异常,其余6例患者均表现为高尿酸血症伴肾功能障碍,其中3例进入终末期肾脏病,2例死于尿毒症。先证者肾脏病理检查表现为肾小管间质慢性病变合并肾小球局灶性硬化,不伴有免疫复合物的沉积。免疫荧光染色结果显示,先证者肾组织小管上皮细胞内有UMOD蛋白强阳性信号聚集,与正常对照及非FJHN导致的慢性间质性肾炎患者比较具有诊断特异性。包括先证者在内共4个受累者进行了基因测序检测,均发现UMOD基因杂合突变c.377G>A,为位于UMOD基因3号外显子的一种新的错义突变。结论:本家系中受累患者呈典型常染色体显性遗传方式,临床表现为高尿酸血症伴早期肾功能受损,肾脏病理表现为非免疫复合物介导的小球硬化及肾间质纤维化,肾小管上皮细胞内有UMOD蛋白的异常积聚,基因检测证实存在新UMOD基因位点突变,FJHN诊断明确。提示对临床上不明原因的高尿酸血症伴特征性病理改变患者,肾组织UMOD蛋白荧光染色是发现FJHN的一种简便方法,有利于减少临床漏诊。Objective To investigate the etiology,clinicopathological changes and genetic variation characteristics of familial juvenile hyperuricemia nephropathy(FJHN)through pedigree investigation and gene test conducted on a patient with FJHN.Methods Clinical data of the proband family members were collected,routine pathological examination of the proband kidney tissue was conducted,and the expression of the Uromodulin(UMOD)protein in the proband kidney tissue was detected by immunofluorescence staining.Peripheral blood specimens of proband and their relatives were collected,and gene sequencing analysis related to urinary system diseases including UMOD was performed by double-stranded DNA probe gene capture and high-throughput sequencing.Results Seven family members in the family were involved and the inheritance method was consistent with autosomal dominant inheritance.Among the seven affected individuals only a 3-year-old child didn't show any clinical abnormalities.All of the remaining six patients had hyperuricemia accompanied with renal dysfunction and three of them were end-stage renal disease and two of them died of uremia.Proband renal pathological results showed chronic tubulointerstitial lesions and focal glomerular sclerosis with no obvious deposition of immune complexes.Immunofluorescent staining showed that strong positive signals of UMOD protein accumulated in the tubular epithelial cells,which was very specific and could be used to differentiate FJHN from other interstial nephritis.A total of four patients including the proband were tested and all had found heterozygous mutation c.377G>A of UMOD gene,a new missense mutation located on exon 3.Conclusion Involved patients in this family present a typical autosomal dominant inheritance pattern,clinically manifested as hyperuricemia with early renal function impairment,renal pathology manifested as non-immune complex-mediated glomerular sclerosis and renal interstitial fibrosis,and there is abnormal accumulation of UMOD protein in renal tubular epithelial cells

关 键 词：高尿酸血症 染色体畸变 家族性青少年高尿酸血症肾病 常染色体显性遗传性肾小管间质性肾病 Uromodulin蛋白 

分 类 号：R725.8[医药卫生—儿科]