一个Fabry病家系的基因突变和临床表型研究  

The research of genotype and phenotype in a family of fabry disease with renal failure

作　　者：熊京[1] 王春丽[1] 朱峰[2] 汪洋[3] 

机构地区：[1]华中科技大学同济医学院附属协和医院肾内科,武汉430022 [2]华中科技大学同济医学院附属协和医院心血管内科,武汉430022 [3]华中科技大学同济医学院附属协和医院急诊科,武汉430022

出　　处：《临床肾脏病杂志》2013年第10期444-448,共5页Journal Of Clinical Nephrology

基　　金：国家自然科学基金（NQ30800532）;教育部博士点基金新教师项目（NQ200804871122）

摘　　要：目的对一个临床表现以肾脏损害为主的Fabry病家系进行调查，分析其基因突变和临床特点。探讨不同突变类型对临床表型的影响。方法收集该例先证者及其家族成员的临床资料。采集先证者及其姐姐和一名健康对照者的外周血，应用荧光底物法检测a半乳糖苷酶A（toga[A）的酶活性；提取血液基因组DNA，PCR分段扩增α—galA基因的7个外显子，产物纯化后进行DNA测序，检测是否存在突变位点。结果①临床调查患者家系发现5名男性患者，均发展至终末期肾脏疾病（endstage renaldisease，ESRD），伴有肢端疼痛、皮肤血管胶质瘤及少汗等Fabry病典型表现；3名女性杂合子，临床表现各异；②regalA活性检测示先证者酶活性明显下降，其姐姐α-galA活性在正常范围；③基因检测发现先证者regalA基因第2外显子的第112个密码子上的碱基胞嘧啶（c）被胸腺嘧啶（T）替代，因此导致由原本翻译的精氨酸变成了半胱氨酸（p．R112C），形成错义突变，从而导致α-galA酶活性的降低或缺乏。结论发现了一个新的Fabry病家系，并明确了该家系的基因突变特点。在此家族中，我们发现除了外胚层组织损害，α—galA基因错义突变p．R112C亦可导致中胚层组织（如肾脏）的严重损害。Objective Fabry disease （FD） is a rare disease due to an X-linked recessive inborn error of glycosphingolipid metabolism resulting from the mutations of the a-galactosidase A （α-gal A） gene. FD is rare in Chinese and the data on clinic and genetic features of FD is still limited. Methods In this study, the a-gal A gene of a Chinese family diagnosed with FD was analyzed for mutations and the genetic features of FD in this family were presented. Results The α-gal A activity of the proband in this family was 0. 03 nmol/ml/h in the whole blood. By PCR amplification and sequencing of the α- gal A gene exons, a single C-to-T transition was identified in codon 112 of exon 2. This C-to-T transi- tion, mapping to position 334 in the cDNA of the α-gal A gene, was a missense mutation predicting a substitution of arginine to cysteine （p. Rl12C） ,which disrupts the normal activity of α-gal A enzyme. No further mutations were found in other exons of the α-gal A gene. In contrast to previous reports, in this family, all of the five male patients developed end-stage renal failure due to this missense muta- tion. Conclusions These findings suggest that the missense mutation, p. Rl12C, in α-gal A gene ablates its activity and results in the development of FD with the renal damage.

关 键 词：肾衰竭 FABRY病 错义突变 

分 类 号：R734.2[医药卫生—肿瘤]