一个早发高血压遗传家系钙敏感受体基因突变点分析  

A novel mutation in the calcium-sensing receptor gene in the Chinese early-onset hypertension family

作　　者：邱颖冬 骆杰伟[1] 朱耀彬 刘桂[1,2] 魏世超 郑星宇[1] 林新富[1] QIU Ying-dong;LUO Jie-wei;ZHU Yao bin;LIU Gui;WEI Shi-chao;ZHENG Xing-yu;LIN Xin-fu(Department of Traditional Chinese Medicine,Fujian Provincial Hospital,Provincial Clinical Medical College,Fujian Medical University,Fuzhou Fujian 350001,China)

机构地区：[1]福建医科大学省立临床医学院,福建省立医院中医科,福建福州350001 [2]福建中医药大学第二临床医学院 [3]福建医科大学附属第一医院中医科

出　　处：《中华高血压杂志》2018年第7期654-660,共7页Chinese Journal of Hypertension

基　　金：福建省自然科学基金项目(2016J01501); 福建省卫生系统中青年骨干人才培养项目(2015-ZQN-ZD-7); 福建省医药卫生科技创新项目(2015-CX-4)

摘　　要：目的应用第二代测序方法筛查一早发高血压遗传家系致病基因突变点,并探讨临床意义。方法选择早发特征的一高血压家系,先证者进行Illumina Miseq目标区域捕获测序及生物信息分析,包括对单基因高血压相关的43个致病基因的编码区及侧翼区进行了检测。之后,对最小等位基因频率(MAF)≤1%的突变多态位点进行聚合酶链反应(PCR)并Sanger测序验证,并与高血压表型连锁分析。结果在家系高血压患者中发现钙敏感受体(CaSR)基因外显子7的2156位置鸟嘌呤(G)突变为腺嘌呤(A),导致第719位的氨基酸由色氨酸(Trp)变为终止密码子,为新发的无义突变,呈杂合型(c.G2156A,p.W719X),预测该突变导致所编码的蛋白质发生截短从而丧失其正常功能。而在无高血压病史家系成员中未发现携带此突变点。家系高血压患者临床表型特点有:面部潮红、易激动,头胀晕,发病年龄18~30岁;舒张压高,舒张压对药物反应不佳;血压对天气变化敏感;在应激状态下(如感染)会出现轻度高血钙症;而在无高血压病史家系成员中未发现这些特点,也没有应激性高血钙症表现。结论CaSR基因的c.G2156A(p.W719X)新发的无义突变可能是此早发高血压家系或应激性高血钙症的遗传病因。Objective To detect the mutation site of pathogenic gene in a hereditary early-onset hypertension family by the next generation sequencing（NGS）and to explore its clinical significance. Methods The proband of the early-onset hypertension family was subjected by Illumina Miseq target region capture sequencing and bioinformatics analysis,including the detection of coding regions and flanking regions of 43 pathogenic genes associated with singlegene related hypertension. Subsequently,the polymerase chain reaction（PCR）and Sanger sequencing verification were performed on mutation polymorphic sites of minor allele frequency（MAF）≤1%,and then a linkage analysis with the phenotype of hypertension was made. Results A novel nonsense mutation（c.G2156 A,p.W719 X）of exon 7 on calcium-sensing receptor（CaSR）gene was found in the hypertension patients in the family,which was heterozygous. The mutation resulted in 719 th amino acids from tryptophan（Trp）into a stop codon,predicting the truncation of encoded protein and lose its normal function. However,there wasn＇t mutation found in the family members without hypertension. The clinical characteristics of the hypertension patients in the family manifested as facial flushing,easy to excitement,dizziness,onset of 18 to 30 years old,high diastolic blood pressure and poor response to drugs,blood pressure sensitive to the change of weather and mild hypercalcemia occurring under stress conditions（such as infection）. While subjects without hypertension had no these clinical characteristics and no stress induced hypercalcemia. Conclusion The novel nonsense mutation c.G2156 A（p.W719 X）on the CaSR might be the genetic cause of the early-onset hypertension family or stress induced hypercalcemia.

关 键 词：早发高血压家系 钙敏感受体 基因突变 高血钙症 

分 类 号：R544.1[医药卫生—心血管疾病]