家族性高胆固醇血症(FH)致病基因的研究进展  

Research progress of genetic causes of familial hypercholesterolemia(FH)

作　　者：陈晨[1] 陆志强[1] 

机构地区：[1]复旦大学附属中山医院内分泌科,上海200032

出　　处：《复旦学报（医学版）》2012年第2期207-211,共5页Fudan University Journal of Medical Sciences

摘　　要：家族性高胆固醇血症(familial hypercholesterolemia,FH)的临床特征为血总胆固醇升高,尤其是低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-c)升高,沉积于组织,形成皮肤或肌腱黄色瘤,导致动脉粥样硬化甚至早发冠心病。FH的发病机制为LDL受体(LDL receptor,LDLR)或apoB基因突变引起LDL受体途径功能缺陷,主要为常染色体显性遗传疾患,具有基因剂量效应;部分患者为常染色体隐性遗传,机制为LDL受体衔接蛋白1(LDL receptor adaptor protein 1,LDLRAP1)失功能型突变,导致LDL内化活性降低。罕见的人类枯草溶菌素转化酶9(proprotein convertase subtilisin/kexin type 9,PCSK9)发生功能型突变也可引起严重的FH表型。PCSK9通过降解LDLR蛋白间接下调LDL受体途径,其失功能突变可致血浆LDL水平下降。因此PCSK9是目前降脂药物的研究热点。Familial hypercholesterolemia （FH） is characterized by raised serum low density lipoprotein cholesterol （LDL-c） levels, which result in excess deposition of cholesterol in tissues, and then lead to atherosclerosis and premature coronary heart disease. The mutations of LDL receptor or apoB play main roles in this disease. FH results from defects in the uptake and degradation of LDL via the LDL receptor pathway. FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDL receptor adaptor protein 1 （LDLRAP1）, which encodes a protein required for internalization of the LDL receptor （LDLR）. Rare gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 （PCSK9） cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally down-regulates the LDLR pathway by indirectly causing degradation of LDLR protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus,PCSK9 is an attractive target for hypolipidemic drugs.

关 键 词：家族性高胆固醇血症(FH) 载脂蛋白B 低密度脂蛋白受体(LDLR) LDL受体衔接蛋白1 (LDLRAP1) 人类枯草溶菌素转化酶9 

分 类 号：R596.2[医药卫生—内科学]