一个家族性高胆固醇血症样表型相关LIPC突变位点的鉴定与三维结构分析

Identification and 3D architecture analysis of the LIPC gene mutation in a pedigree with familial hypercholesterolemia-like phenotype

目的:对一个家族性高胆固醇血症样表型(FHLP)家系的易感基因突变位点进行鉴定,并分析蛋白三维结构。方法:该研究为病例系列研究。病例来源于北京安贞医院2019年4月4日门诊收治的一疑似家族性高胆固醇血症家系。通过全外显子测序,对先证者进行易感基因突变位点筛查,采用聚合酶链式反应对先证者亲属进行突变位点验证。通过Discovery Studio 4.0和PyMoL 2.0软件对突变前后蛋白的结构与功能进行分析和预测。结果:该家系患者表现为以总胆固醇(TC)升高为主要特征的血脂异常。易感基因筛查结果显示先证者及其父亲和弟弟在突变脂肪酶C(LIPC)基因的第8外显子存在一个杂合单核苷酸多态性位点LIPC:c.1330C>T,导致LIPC蛋白序列第444位的精氨酸(Arg)被半胱氨酸(Cys)替代(Arg444Cys)。该家系中携带该突变的成员表现为TC升高,而未携带该突变的先证者母亲血脂正常,提示LIPC:c.1330C>T可能是易感基因突变位点。蛋白质功能预测提示该突变主要影响其配体结合功能,对催化功能影响有限。结论:LIPC:c.1330C>T是新的FHLP易感基因突变位点。

ObjectiveTo identify and analyze 3D architecture of the mutational sites of susceptible genes in a pedigree with familial hypercholesterolemia-like phenotype(FHLP).MethodsThis is a case series study.A pedigree with suspected familial hypercholesterolemia was surveyed.The proband admitted in Beijing Anzhen Hospital in April 2019.Whole-exome sequencing was performed to determine the mutational sites of susceptible genes in the proband.Polymerase chain reaction(PCR)sequencing was used to verify the pathogenic variant on proband′s relatives.The structural and functional changes of the proteins were analyzed and predicted by Discovery Studio 4.0 and PyMol 2.0.ResultsThe patients in the pedigree showed abnormal lipid profiles,especially elevated levels of total cholesterol(TC).The genetic screening detected the c.1330C>T SNP in the exon 8 of lipase C(LIPC)gene,this mutation leads to an amino acid substitution from arginine to cysteine at position 444(Arg444Cys),in the proband and proband′s father and brother.In this family,members with this mutation exhibited elevated TC,whereas lipid profile was normal from the proband′s mother without this mutation.This finding indicated that LIPC:c.1330C>T mutation might be the mutational sites of susceptible genes.The analysis showed that Arg444Cys predominantly affected the ligand-binding property of the protein,but had a limited impact on catalytic function.ConclusionLIPC:c.1330C>T is a new mutational site of susceptible genes in this FHLP pedigree.