迟发性家族性局灶节段肾小球硬化的足细胞分子基因突变研究  

Mutations of podocyte molecules in patients with late onset familial focal segmental glomerular sclerosis

作　　者：朱斌[1] 王朝晖[1] 潘晓霞 任红[1] 张文[1] 王伟铭[1] 徐耀文[1] 潘春明[1] 盛燕 宋怀东 陈楠[1] 

机构地区：[1]上海交通大学医学院附属瑞金医院肾脏科,200025 [2]医学基因组学国家重点实验室

出　　处：《中华肾脏病杂志》2008年第9期619-626,共8页Chinese Journal of Nephrology

基　　金：上海市卫生局重点学科基金（05Ⅲ001）;上海市教委重点学科建设基金（T0201）;上海市卫生局重点课题（2003ZD002）

摘　　要：目的了解迟发性家族性局灶节段肾小球硬化（FSGS）的足细胞分子基因致病突变特点。方法研究对象为上海瑞金医院肾脏科1997年9月至2007年10月收集的31个迟发性家族性FSGS家系。诊断标准：（1）成员年龄大于12岁；（2）1个家系中有2例或2例以上患者经肾活检证实为FSGS，或家系成员中有1例肾活检证实为FSGS，另有1例成员有蛋白尿或肾功能不全。100例健康人为对照组。外周血基因组DNA经PCR扩增后直接对NPHS2、ACTN4、TRPC6基因行测序分析。结果发现ACTN4基因新错义突变L316P，该家系患病成员起病年龄平均（38．7±7．4）岁，肾功能损害进展相对缓慢，家系3例患病成员均为突变杂合子。发现TRPC6基因新杂合错义突变Q889K，该家系患者起病年龄平均（38．0±4．2）岁，肾功能损害进展也较缓慢，家系中临床表现存在个体差异，家系中3例患病成员均为突变杂合子。发现TRPC6静止突变G467G。所有家系中未发现NPHS2致病突变。健康对照组200条染色体亦未发现以上突变。结论在31例迟发性FSGS家系中发现2个家系携带致病相关突变：ACTN4新突变L316P和TRPC6新突变QS89K。在中国人群家族性迟发性FSGS中，ACTN4及TRPC6基因突变是致病原因之一，尚未发现NPHS2相关致病突变。Objective To investigate the mutations of podocyte molecules in patients with late onset familial focal segmental glomerular sclerosis （FSGS）. Methods Thirty-one pedigrees of late onset familial FSGS in Department of Nephrology, Shanghai Ruijin Hospital from Sep 1997 to Oct 2007 were enrolled in this study. The diagnosis standard of familial FSGS was as follows：（1） the age of presentation was more than 12 years old. （2） in one pedigree, two or more individuals were proven as FSGS by renal biopsy, or at least one was proven to be FSGS by renal biopsy, the others presented renal insufficiency or proteinuria without precise causes. One hundred unrelated healthy people were screened as control group. Genomic DNA extracted from peripheral blood cells were amplified by PCR and then sequenced for mutations of NPHS2, ACTN4 and TRPC6. Results A novel missense heterozygotic mutation L316P of ACTN4 was identified in one pedigree. The mean onset age of the affected members of this pedigree was （38.7±7.4） years old and their kidney injury progress was slow. Proteinuria of the proband＇s brother was not improved by immunosuppressor. All 3 affected members of this family had such heterozygotic mutation. A novel missense heterozygotie mutation Q889K of TRPC6 was found in another pedigree. The mean onset age of the affected members in this pedigree was （38.0±4.2） years old. Three members presenting renal disease in this family all had sueh heterozygotie mutation but with different clinical manifestations. A quiescent mutation G467G of TRPC6 was also identified. Above variants were not found in healthy controls. No NPHS2 mutation was found to cause familial FSGS in these pedigrees. Conclusions A novel mutation L316P of ACTN4 and a new mutation Q889K of TRPC6 are identified in Chinese patients of late onset familial FSGS. No NPHS2 mutation is found to induce FSGS in these pedigrees.

关 键 词：肾小球硬化症 局灶性 系谱 突变 NPHS2 ACTN4 TRPC6 

分 类 号：R692.6[医药卫生—泌尿科学] R734.2[医药卫生—外科学]