一家族性高胆固醇血症家系低密度脂蛋白受体突变及临床表型研究
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摘要
[目的]
家族性高胆固醇血症(familial hypercholesterlolemia FH)是一种常见的常染色体单基因显性遗传性疾病,以血浆总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)水平明显增高为特征,是引起动脉粥样硬化和早发冠心病的最重要危险因素。其发病机制是由于低密度脂蛋白受体(low density lipoproteinreceptor,LDLR)突变,导致血LDL-C清除障碍,血浆LDL-C水平明显增高。为探讨FH患者低密度脂蛋白受体可能的致病基因,分析FH患者LDLR突变与临床表型之间的关系,探讨FH的分子病理机制,本研究采集了一个经临床诊断为FH的家系,对其家系成员进行体检、血脂等临床检测分析,眼底、心电图、心脏血管彩色超声多普勒检查,并对其载脂蛋白B100(ApoB100)基因及LDLR基因的突变进行了研究。
[方法]
以一个家族性高胆固醇血症家系为研究对象,对其成员进行常规体格检查、血脂等生化指标的测定,并对先证者亲属进行了心电图、眼底、心血管超声等更为细致的检查。采用聚合酶链反应(polymerase chain reaction,PCR)扩增启动子和全部18个外显子片段,产物电泳鉴定后直接序列分析,检测LDLR基因突变,结果与GenBank公布的该基因正常序列比对,找出突变并检索FH突变数据库。(www.ucl.ac.uk/fh),以确定是否为新突变。同时PCR扩增ApoB100基因包含3500、3501、3531和3480位点的序列,产物电泳鉴定后测序,以排除家族性载脂蛋白B100缺陷症(Familial defective apolipoprotein B,FDB)。
[结果]
临床查体及心血管超声检查发现先证者及其弟妹、父母均存在不同程度的动脉硬化。DNA测序发现先证者及同胞LDLR基因第10外显子的第1581位碱基发生G＞A纯合突变,导致第496位密码子由GGG改变为GAG其编码氨基酸由甘氨酸(Gly)变为谷氨酰胺(Glu)。其父母相同位点表现为杂合突变,家系第一代存活成员未见突变。同时未检测出先证者ApoB100 R3500Q、R3531C、R3501W和R3480W突变。
[结论]
1.先证者及其弟妹、父母为FH患者,均存在不同程度的动脉硬化。
2.该患者ApoB100基因包括3500、3531、3501和3480位点在内的片段未见突变,可排除患家族性载脂蛋白B100缺陷症(FDB)的可能性。
3.本研究通过对一例临床诊断家族性高胆固醇血症患者相关基因的分析,发现先证者及其弟妹LDLR基因第10外显子1581位点G＞A纯合错义突变(G496E),G496E为新突变,为该家系致病性突变。突变分别来自于父母的遗传。
Objective
Familial hypercholesterolemia(FH) and familial defective apolipoprotein B-100 (FDB) are autosomal codominant diseases characterized by elevated LDL cholesterol levels and premature coronary artery disease.Mutations of the LDL-receptor and apolipoprotein B genes,which affect the binding domains of their protein products, are the causal defects.Securing the diagnosis of these conditions by molecular assays is important because it mandates early intervention for coronary risk reduction..The purpose of this study is to investigate the low density lipoprotein receptor(LDLR)gene and apolipoprotein B gene mutation in a Chinese family with familial hypercholesterolemia(FH) and make a discussion on the relationship between genotype and phenotype.
Methods
After physical examination,the the kindreds underwent ECG and ultrasound checks.Blood samples were tested for lipid profiles.The promoter and all eighteen exons of LDLR gene were investigated by using PCR and agarose gel electrophoresis in combination with DNA sequence analysis.The results were compared with the normal sequences in GenBank and FH database(www.ucl.ac uk/fh ) to find mutations.In addition,the apolipoprotein B100 gene for known mutations(R3500Q,R3531C,R3501W and R3480W)that cause familial defective ApoB100(FDB)was also tested using the same method.
Results
A novel homozygous G＞A mutation at the 1581bp of exon 10 was detected in the proband and his siblings.It cause a substitution of amimo acid Glu to Gly at codon 496.A novel heterozygous G＞A mutation at the 1581bp of exon 10 was detected in his parents.No mutations of R3500Q,R3531C,R3501W and R3480W of ApoB100 were observed.ECGs were normal.Atherosclerosis were found in all family members by ultrasound checks.
Conclusions
The homozygous G＞A mutation at the 1581bp of exon 10 was first determined in our country.The change of amino acid Glu to Gly is responsible for FH of the family. The type of the gene mutation was not found in the GenBank.It's a new type of LDLR mutation.
家族性高胆固醇血症(familial hypercholesterlolemia FH)是一种常见的常染色体单基因显性遗传性疾病,以血浆总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)水平明显增高为特征,是引起动脉粥样硬化和早发冠心病的最重要危险因素。其发病机制是由于低密度脂蛋白受体(low density lipoproteinreceptor,LDLR)突变,导致血LDL-C清除障碍,血浆LDL-C水平明显增高。为探讨FH患者低密度脂蛋白受体可能的致病基因,分析FH患者LDLR突变与临床表型之间的关系,探讨FH的分子病理机制,本研究采集了一个经临床诊断为FH的家系,对其家系成员进行体检、血脂等临床检测分析,眼底、心电图、心脏血管彩色超声多普勒检查,并对其载脂蛋白B100(ApoB100)基因及LDLR基因的突变进行了研究。
[方法]
以一个家族性高胆固醇血症家系为研究对象,对其成员进行常规体格检查、血脂等生化指标的测定,并对先证者亲属进行了心电图、眼底、心血管超声等更为细致的检查。采用聚合酶链反应(polymerase chain reaction,PCR)扩增启动子和全部18个外显子片段,产物电泳鉴定后直接序列分析,检测LDLR基因突变,结果与GenBank公布的该基因正常序列比对,找出突变并检索FH突变数据库。(www.ucl.ac.uk/fh),以确定是否为新突变。同时PCR扩增ApoB100基因包含3500、3501、3531和3480位点的序列,产物电泳鉴定后测序,以排除家族性载脂蛋白B100缺陷症(Familial defective apolipoprotein B,FDB)。
[结果]
临床查体及心血管超声检查发现先证者及其弟妹、父母均存在不同程度的动脉硬化。DNA测序发现先证者及同胞LDLR基因第10外显子的第1581位碱基发生G＞A纯合突变,导致第496位密码子由GGG改变为GAG其编码氨基酸由甘氨酸(Gly)变为谷氨酰胺(Glu)。其父母相同位点表现为杂合突变,家系第一代存活成员未见突变。同时未检测出先证者ApoB100 R3500Q、R3531C、R3501W和R3480W突变。
[结论]
1.先证者及其弟妹、父母为FH患者,均存在不同程度的动脉硬化。
2.该患者ApoB100基因包括3500、3531、3501和3480位点在内的片段未见突变,可排除患家族性载脂蛋白B100缺陷症(FDB)的可能性。
3.本研究通过对一例临床诊断家族性高胆固醇血症患者相关基因的分析,发现先证者及其弟妹LDLR基因第10外显子1581位点G＞A纯合错义突变(G496E),G496E为新突变,为该家系致病性突变。突变分别来自于父母的遗传。
Objective
Familial hypercholesterolemia(FH) and familial defective apolipoprotein B-100 (FDB) are autosomal codominant diseases characterized by elevated LDL cholesterol levels and premature coronary artery disease.Mutations of the LDL-receptor and apolipoprotein B genes,which affect the binding domains of their protein products, are the causal defects.Securing the diagnosis of these conditions by molecular assays is important because it mandates early intervention for coronary risk reduction..The purpose of this study is to investigate the low density lipoprotein receptor(LDLR)gene and apolipoprotein B gene mutation in a Chinese family with familial hypercholesterolemia(FH) and make a discussion on the relationship between genotype and phenotype.
Methods
After physical examination,the the kindreds underwent ECG and ultrasound checks.Blood samples were tested for lipid profiles.The promoter and all eighteen exons of LDLR gene were investigated by using PCR and agarose gel electrophoresis in combination with DNA sequence analysis.The results were compared with the normal sequences in GenBank and FH database(www.ucl.ac uk/fh ) to find mutations.In addition,the apolipoprotein B100 gene for known mutations(R3500Q,R3531C,R3501W and R3480W)that cause familial defective ApoB100(FDB)was also tested using the same method.
Results
A novel homozygous G＞A mutation at the 1581bp of exon 10 was detected in the proband and his siblings.It cause a substitution of amimo acid Glu to Gly at codon 496.A novel heterozygous G＞A mutation at the 1581bp of exon 10 was detected in his parents.No mutations of R3500Q,R3531C,R3501W and R3480W of ApoB100 were observed.ECGs were normal.Atherosclerosis were found in all family members by ultrasound checks.
Conclusions
The homozygous G＞A mutation at the 1581bp of exon 10 was first determined in our country.The change of amino acid Glu to Gly is responsible for FH of the family. The type of the gene mutation was not found in the GenBank.It's a new type of LDLR mutation.
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