3个遗传性出血性毛细血管扩张症家系临床和基因诊断研究  

Clinical characteristics and molecular mechanisms of hereditary hemorrhagic telangiectasis( HHT) in 3 families

作　　者：迟昆 姜林林[1] 陆晔玲[2] 戴菁[2] 丁秋兰[2] 王学锋[2] 王鸿利[1] 

机构地区：[1]上海交通大学医学院附属瑞金医院,上海血液学研究所医学基因组学国家重点实验室,上海200025 [2]上海交通大学医学院附属瑞金医院临床检验科,上海200025

出　　处：《中国输血杂志》2013年第12期1193-1197,共5页Chinese Journal of Blood Transfusion

基　　金：上海市重点学科建设计划(12GWZX0202)

摘　　要：目的对遗传性出血性毛细血管扩张症(HHT)家系做临床诊断并探索其分子发病机制。方法收集3个疑似HHT患者的病史、临床表型和家族史等基本资料,对患者凝血功能相关指标做实验室检测,排除凝血系统异常。采用直接测序法对HHT相关基因ENG和ACVRL1做序列分析,寻找致病突变;将所发现的突变重新扩增PCR产物反向测序以证实。比对新的基因突变,筛查100个正常人、单核苷酸多态性数据库、人类基因突变数据库和HHT基因变异数据库以排除多态性。结果 3个家系中均存在出血、毛细血管扩张、阳性家族史等HHT典型临床特点,凝血功能均未发现异常。基因测序显示突变均存在于ACVRL1基因上,3个家系携带的突变分别是g.18349C>A,p.Ser462X、g.12876G>T,p.Glu281X和g.12079G>T,p.Val228Phe,其中g.18349C>A,p.Ser462X和g.12079G>T,p.Val228Phe为新发致病突变。在100个正常人和数据库中均未发现相关突变;3个突变均导致ACVRL1基因编码的ALK-1蛋白激酶功能区内的氨基酸发生改变。结论在这3个有典型HHT表现的家系中,发生在ALK-1蛋白激酶功能区内氨基酸的改变是其分子水平的致病原因。Objective To disclose the molecular mechanisms of hereditary hemorrhagic telangiectasis（ HHT）. Methods The medical history,clinical information and family history of 3 suspected HHT families were collected after informed consent. Laboratory inspection was performed to exclude other possible pathogenesis related to coagulation abnormalities. All the exons and flanking sequence of the 2 HHT related genes,ENG and ACVRL1,respectively,were amplified and sequenced directly. Reverse sequencing was employed to justify the mutations we found. Comparing with 100 normal people,database of SNP,the human gene mutation database and HHT mutation database,we excluded polymorphism and determined whether the mutations were novel. Results The typical clinical characteristics of HHT such as bleeding,telangiectasis and positive family history existed in all 3 families. Abnormalities of coagulation system were found in none of the patients. The results of sequencing found 3 mutations（ g. 18349C A,p. Ser462X,g. 12876G T,p. Glu281X and g. 12079G T,p. Val228Phe） of ACVRL1 in the 3 families. Of the mutations,g. 18349C A,p. Ser462X and g. 12079G T,p. Val228Phe were novel. None of the 3 mutations were polymorphism after blasting with 100 normal people and related database. All the 3 mutations led to amino acid alterations in the protein kinase region of ALK-1 coded by ACVRL1. Conclusion Amino acid alterations in protein kinase region of ALK-1 led to typical HHT in 3 families.

关 键 词：出血性毛细血管扩张症 遗传性 ACVRL1基因 突变 激酶功能区 

分 类 号：R554.9[医药卫生—血液循环系统疾病] R446.112[医药卫生—内科学]