同时伴有LDLRAP1及ABCG8基因异常的家族性高胆固醇血症一家系的临床及分子生物学特征  

Clinical and molecular characteristics of a family with familial hypercholesterolemia with LDLRAP1 and ABCG8 gene abnormality

作　　者：李佳明[1] 彭真萍 丁秋兰[2] 王学锋[2] 金佩佩[2] Li Jiaming;Peng Zhenping;Ding Qiulan;Wang Xuefeng;Jin Peipei(Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Department of Blood Transfusion,Shanghai 200025,China;Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Department of Clinical Laboratory Medicine,Shanghai 200025,China)

机构地区：[1]上海交通大学医学院附属瑞金医院输血科,上海200025 [2]上海交通大学医学院附属瑞金医院检验科,上海200025

出　　处：《中华检验医学杂志》2022年第3期252-259,共8页Chinese Journal of Laboratory Medicine

基　　金：国家自然科学基金(81601823,81900129)。

摘　　要：目的探究同时伴有低密度脂蛋白受体衔接蛋白1(LDLRAP1)及胆固醇转运蛋白三磷酸腺苷结合盒转运体G8(ABCG8)基因异常的家族性高胆固醇血症(FH)一家系的临床及分子生物学特征。方法2020年9月于上海交通大学医学院附属瑞金医院收治1例FH患者,采集该家系成员外周静脉血样本,检测血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C);用高效液相色谱法检测血清豆固醇和谷固醇含量。二代基因测序检测先证者及家系成员基因变异情况。采用Pymol软件对基因变异位点进行致病性分析,并使用Uniprot Modelling软件行蛋白结构建模。结果先证者表现为贫血合并多部位黄色瘤、早发急性冠状动脉综合征。冠状动脉造影示冠状动脉三支严重病变;腹部超声示脾肿大;血涂片示异型红细胞、大血小板散在可见;血清TC、LDL-C、豆固醇和谷固醇浓度均升高[分别为8.54 mmol/L(正常值2.3~5.7 mmol/L)、4.84 mmol/L(正常值1.3~4.3 mmol/L)、44μmol/L(正常值1.0~10μmol/L)、28μmol/L(正常值1.0~15μmol/L)]。基因测序示:LDLRAP1:NM;15627.2:exon 4 c.415 C>T(p.Q139X),该纯合突变形成的蛋白截断体丢失多个稳定蛋白结构区域,不具备正常功能。同时,先证者发现ABCG8基因变异:exon13 c.1895T>C(p.V632A),exon8 c.1199C>A(p.T400K)。2例家系成员HDL-C增高(Ⅱ5:2.33 mmol/L,Ⅱ6:2.96 mmol/L);3例带ABCG8基因变异的成员豆固醇(Ⅱ8:23μmol/L,Ⅱ7:24μmol/L,Ⅰ2:18μmol/L)、谷固醇(Ⅱ8:41μmol/L,Ⅱ7:33μmol/L,Ⅰ2:45μmol/L)轻度增高。结论同时伴有LDLRAP1及ABCG8基因异常的FH患者,可出现植物固醇浓度异常,其临床表现更加复杂,应综合考虑家族史及LDL-C、植物固醇水平及基因检测结果。Objective To study the clinical and molecular characteristics of a family with familial hypercholesterolemia(FH)with LDLRAP1 and ABCG8 gene abnormality.Methods In September 2020,one case of FH was included in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;peripheral venous blood samples of members of the family were collected to detect serum total cholesterol(TC),triglycerides(TG),and low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)indicators;use high-performance liquid chromatography to detect serum stigmasterol and sitosterol content;perform second-generation gene sequencing to detect gene mutations in probands and family members;use Pymol software to detect gene mutations point for pathogenicity analysis,and use Uniprot Modelling software to perform protein structure modeling.Results The patient presented with anemia,multiple xanthomas and early-onset acute coronary syndrome.The coronary angiography showed severe coronary artery lesions;abdominal ultrasound showed splenomegaly;blood smear showed shaped erythrocytes and large platelets.The level of serum TC,LDL-C,stigmasterol and sitosterol was 8.54 mmol/L(2.3-5.7 mmol/L),4.84 mmol/L(range of normal value 1.3-4.3 mmol/L),44μmol/L(1.0-10μmol/L),28μmol/L(1.0-15μmol/L),respectively;LDLRAP1 gene mutation was found:exon4 c.415C>T:p.Q139X;the truncated protein formed by this homozygous mutation lost multiple stable protein structure regions,which can not have a normal function.At the same time,ABCG8 gene mutations were also found:exon13 c.1895T>C(p.V632A)and exon8 c.1199C>A:p.T400K.Two cases of family members had a mild increase in HDL-C(Ⅱ5:2.33 mmol/L,Ⅱ6∶2.96 mmol/L),3 cases carrying the ABCG8 gene mutations had a slight increase in stigmasterol(Ⅱ8:23μmol/L,Ⅱ7:24μmol/L,Ⅰ2:18μmol/L)and sitosterol(Ⅱ8:41μmol/L,Ⅱ7:33μmol/L,Ⅰ2:45μmol/L),suggesting that its association with the concentration of plant sterols.Conclusions FH patients with LDLRAP1 and ABCG8 gene abnormalitie

关 键 词：家族性高胆固醇血症 植物固醇血症 贫血 基因突变 

分 类 号：R589.7[医药卫生—内分泌]